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With the Silver Conference and Johto behind them, Ash, Misty, and Brock are heading towards Pallet Town and decide to make a stop in Viridian City. Brock is the most excited, simply because it means that he'll get to see Nurse Joy. Misty is, as usual, tired of Brock's misguided romantic efforts.

Ash deposits his Poké Balls at the Pokémon Center, and asks Nurse Joy if she remembers him. However, it turns out that this Nurse Joy isn't the one he met all that time ago, but a new one. She has heard about him though, and tells Misty that she has received an urgent call from Cerulean City. Misty is confused as to why anyone would be calling her from there.

Getting to a phone, Misty finds out the call is from her sisters. It turns out all three are going on an around-the-world trip that they won third place in a beauty contest, and therefore need Misty to take over the Gym while they are away. Misty can't believe what she's hearing, and is angry when Ash and Brock comment on how lucky the sisters are winning the trip. Misty objects about having to take over for her sisters, but Ash, not seeing Misty has other reasons for her objections, tells her that it's only temporary. Nurse Joy then surprises Misty with her bike! It turns out the previous Nurse Joy was able to fix it good as new. Seeing the bike brings back a lot of memories for Misty. Misty remembers how her journey with Ash began, when he stole the bike and ended up destroying it. Ash happily comments on how good Nurse Joy did in the restoration, and that Misty can get back to Cerulean City even quicker. This causes Misty's feelings to become hurt. After Ash asks why she was so grouchy, Misty runs out of the Pokémon Center. Ash is confused by Misty's reaction, and Brock points out that Misty may have expected to continue traveling with them.

Misty wanders the streets of Viridian City very sadly, and comments on how Ash doesn't seem to understand or care that the trio will be splitting up. However, around the corner are three Trainers waiting for her. They ask Misty if all her friends have abandoned her, angering Misty even further. Misty asks who they are, and the three introduce themselves as Viridian City's top Trainers; Kim, Kail, and Kai, theInvincible Pokémon Brothers! Misty mocks them by word play on "invincible" with "invisible", telling them to disappear. The leader Kim continues to irritate Misty, who then challenges them to a Pokémon battle.

In a nearby field, Misty and Kim prepare to battle one-on-one. Misty sends out her Politoed and Kim his Hitmonchan. Misty orders a Water Gun, and Politoed is easily able to knock Hitmonchan to the ground. Misty mocks them into changing their names (from the Invincible Brothers), which then provokes Kail and Kai to send out their Pokémon, Hitmonlee and Hitmontop. The three fighting Pokémon surround Politoed, and Misty calls them out on cheating, stating she can't battle fairly three-on-one. However, she is saved when Ash and Brock arrive to make the match fair. Pikachu is able to get Hitmontop with a Thunderbolt, and Brock sends out Forretress, who gets Hitmonlee with a Rapid Spin. Misty is glad to see her friends again, but angrily tells them she could have handled it. Ash and Brock tell her that they knew she could, but they wanted one last battle with the three of them. Ash then tells Misty that she's a great Water Pokémon Trainer, and he knows she can win the battle. Misty is touched by Ash's kind words, and with her faith in their friendship restored, she orders Politoed to use Bubble Attack which devastates Hitmonchan. Pikachu and Forretress then continue their assault on the other two, much to the brothers' dismay.

As the battle rages, Team Rocket appear, and Jessie and James comment on the brothers losing. Meowth cuts in, and on his command Wobbuffet presses a button which causes two goals to appear on opposite ends of the field. The Trainers all notice this, and much to their horror the goals start to come together trapping Ash, Misty, Brock, the brothers, and all the Pokémon inside. The brothers become distraught, claiming to be on Team Rocket's side. This reveals that the three were hired by Team Rocket to battle and tire Ash and the gang out. However, since they failed, not only will they not be getting paid (not that they were going to get paid anyway), but Team Rocket will take their Pokémon along with the others. Fortunately, Kim (having a pair of scissors handy) cuts the net away, releasing everyone. The brothers and their Pokémon quickly surround Team Rocket, and begin to cause a fuss over their money, much to Jessie's annoyance. This distraction and the brothers' destruction of the net allow Ash, Misty, and Brock to escape. They order Pikachu, Politoed, and Forretress to triple-team Team Rocket, the brothers and their Pokémon, who are all sent blasting off.

With the excitement over, Ash tells Misty how great it was watching her battle, and she thanks him. Ash informs her that he and Brock brought her bike, and Misty's excitement quickly diminishes. On the path towards Pewter and Cerulean, Misty tells Ash not to forget to look after himself and Pikachu. She also tells Brock to try to not fall in love with all the girls, which makes him laugh. She then says that she needs to tell Ash one more thing, "Just keep on doing your best." Ash asks what she means, and Misty sadly responds by saying that it's going to be different without her there.

She then remembers how she first met Ash, accidentally fishing him out of a lake and angrily pointing him in the direction of the Viridian City Pokémon Center. She also remembers all the experiences she's shared with Ash, Brock, and Tracey as they travelled through Kanto, the Orange Islands, and Johto, as well as the joys, the struggles, the triumphs, the fun, the hardships, the excitement, and most of all the adventure, which now has to end.

She also recalls how it was an accident that she met Togepi, but Ash tells her that he thinks she's wrong that it was accidental that he happened to meet her of all people. He tells her that he believes that no matter what, they were always meant to meet and become friends. Brock agrees, and tells them that after all their adventures they've all become best friends. Misty and Ash happily agree and continue down the path.

Eventually the path splits into three with one route heading towards Pallet Town, another heading towards Cerulean City, and the third heading towards Pewter City. Ash and Misty start to say their goodbyes, when Brock suddenly butts in, telling them that he just remembered that he received an e-mail and needs to return to Pewter City. Ash asks how Brock could forget something like that, and Misty understands that maybe he didn't want to go.

Now the time has come for all three to part ways and head for their respective homes. The three bid each other farewell, and then Misty and Brock set off. With his friends gone, Ash starts to say the words he didn't feel he could, but suddenly Misty and Brock are back in front of him ready to hear it. Ash tells them they shouldn't sneak up on him, and Brock says that they returned to give Ash some presents. Brock gives Ash a small picnic complete with cutlery, while Misty gives him a handkerchief to wrap it in. Ash is touched by their gesture and begins to cry. With that, the three best friends separate, and Ash, very upset about his long-time companions leaving, runs the rest of the way home.

After a good night's sleep, Ash and Pikachu are happily eating their breakfasts, when Ash's mom mentions to him that Gary arrived back into town himself a couple of days ago. Ash is eager to meet up with his former rival and newfound friend, and quickly leaves with Pikachu. Delia comments to Mimey that she always misses him when he leaves on an adventure.

Getting to Professor Oak's Laboratory, Ash is dismayed when he learns that Gary has already left. Tracey tells Ash that Gary didn't mention where he was going, only that he woke up saying that he was feeling inspired and quickly left before being asked what he meant. Professor Oak mentions that Gary must have wanted to make a fresh start, as he left all of his Pokémon besides his Blastoise at the lab before leaving, and that they have no idea when they'll even see him again.

Gary is just about to leave Pallet Town behind, when Ash catches up to him. The two friends greet each other warmly, and Ash asks Gary what his hurry is. Gary tells Ash that he just feels he needs to keep moving, and that there's still a lot of traveling to do and a lot more to learn about Pokémon. Gary then asks Ash what he plans to do now, and Ash is forced to admit he doesn't know. Gary tells Ash that as he hasn't been home for a long time, that he should wait a while and really think about it. Gary starts to leave, but now it's Ash's turn to give a present to a departing friend, and gives Gary his half of the broken Poké Ball back. Gary thanks Ash, and sets off on his journey.

Sitting on a tree, Ash tells Pikachu he doesn't like the feeling of being alone, and still isn't sure about what to do next. Suddenly Pikachu alerts Ash, who then looks up in the sky and spots a sparkle. To Ash's amazement, it's Ho-Oh! Watching it fly away, Ash notices it's heading towards the Hoenn region. He knows that Hoenn has a lot of Pokémon he's never seen before, and a lot of battles awaiting him. Suddenly Ash feels his spirit return, and decides to do like Gary and make a fresh start and head to Hoenn. He starts to run home, but falls into a classic Team Rocket pitfall trap.

Ash comments on how he was not "prepared" for the fall, and Jessie goes into her lines of the motto. James mentions that the pit is extra deep, and the three have gone back to the classic plan of snaring Pikachu. James calls out Weezing to send a SmokeScreen down the pit. Soon the entire area is filled with smoke causing Ash and Pikachu to start choking. Ash tries to think of something to do, and remembers Misty and Brock's final words and parting gifts. He gets an idea, and after fishing them out of his backpack, has Pikachu cover its mouth with the handkerchief given to him by Misty while he climbs out with the cutlery given to him by Brock. As he climbs out of the pit, he realizes that he is never alone. Ash springs from the pit trap and confronts Team Rocket, informing them that his friends will always be with him. Ash orders Pikachu to hit them with a Thunderbolt, blasting them off yet again. With the dust clearing, Ash looks at the gifts from Brock and Misty, thanking them. He looks up into the sky and comments on the beginning of another journey to become the greatest Pokémon Master.

Back home, Ash tells Professor Oak and Tracey that he has decided to do the same as Gary and leave all of his Pokémon besides Pikachu at the lab. Professor Oak guesses that Ash is heading to Hoenn, and Ash tells him that he plans to meet Professor Birch in Littleroot Town. Tracey agrees with Ash's idea because of Professor Birch being famous for his field work. Ash thanks his friend, when Delia arrives with new clothes and a new backpack for her son, having guessed he would be leaving soon. She also has his ticket for the ferry that departs from the Seafoam Islands to the Hoenn region. Professor Oak gives Ash a brand new Pokédex that contains all the information on the Pokémon that reside in the Hoenn region. Tracey also tells Ash he can count on him to take care of his Pokémon while he's away. With a renewed sense of determination, Ash gets ready to set off for Hoenn, knowing that a brand new set of adventures await him.