Introduced as the son and reincarnation from the demon Piccolo Daimaoh, Piccolo Jr. plans to continue his father's mission of world domination, and avenge his death at the hands of Goku. He Jr. enters the 23rd World Martial Arts Tournament under the alias "Ma Junior" (魔Jr.(マ ジュニア), Demon Jr?). Piccolo fights Goku, but is defeated in the final round. Five years later, Piccolo is confronted by an alien named Raditz. Realizing the Saiyan would thwart his plans for world domination, Piccolo teams up with Goku in an attempt to stop Raditz from destroying the Earth. When the two arch rivals team up, Piccolo is able to defeat Raditz, but at the cost of Goku's life. Piccolo remains amazed with the powers from Goku's son, Son Gohan, and trains him to fight against the two Saiyan who will invade Earth.
When the Saiyan arrive a year later, Piccolo's fondness toward Gohan results in him receiving of one of Nappa's attacks aimed to Gohan, which results in the death of Kami and the Dragon Balls. After the Saiyans are defeated, Gohan and others travel to Piccolo's homeworld Namek to revive those who died against the Saiyans with the Namekian Dragon Balls. Piccolo is resurrected on Planet Namek to help Goku and others defeat the evil Frieza. Despite his massive power increase and going head to head with Frieza's second tranformation, Frieza tranforms and Piccolo is defeated and severely injured by Frieza, leaving Goku to defeat him alone. Piccolo is restored to health, and waits a year until Goku arrives back on Earth. He then trains with Goku and Gohan for three years to prepare for a battle against two powerful androids created by the Red Ribbon to kill Goku.
After being defeated by Android #17 and Android #18, Piccolo seeks to unite with Kami, and gain another massive increase in power. After uniting with Kami, Piccolo becomes aware of a more dangerous threat named Cell. Before his second encounter with Cell, Piccolo once again battles the androids, except this time he battles #17 one on one. After a somewhat even match, Cell arrives on the battle scene and needing to absorb the androids to complete his power, Piccolo is nearly killed by Cell, and he is forced to participate in a Martial Arts Tournament created by Cell called the Cell Games where he fights one of the seven Cell Juniors that are created by Cell, who are later destroyed by Gohan.
Seven years later, Piccolo acts as a trainer to Son Goten, Goku's second son, and Trunks, Vegeta's son, and their fused form Gotenks. Piccolo trains the boys in fighting the evil creature Majin Buu, but is later absorbed by Buu along with Gotenks and Gohan and incorporated into his being. He is later freed by Goku and Vegeta, and he later gives his energy to Goku's Super Spirit Bomb, which Goku uses to defeat Buu once and for all.
In Dragon Ball GT he is severely injured by Gohan while he was possessed by Baby and later dies with Earth in order to destroy the Black Star Dragon Balls. He goes to Heaven but then requests he is sent to Hell in order to free Goku when he is imprisoned there. He can be seen putting Hell in order and protecting the rulers there. In the final episode, Goku stops in Hell to see Piccolo. He tells Piccolo that he will be leaving and that they are glad they met and teamed up. He also says that he has become a good friend and he will get out of Hell someday. They shake hands and Goku leaves while Piccolo stays behind.