The 38-year-old arrives at Home Park aiming to right the wrongs of his nightmare Birmingham City spell, where he was sacked from his post after just 15 matches in charge in January.
Rooney won just two matches at the Blues helm after replacing John Eustace - a move which drew confusion and criticism at the time - and his poor spell contributed to Birmingham's relegation from the Championship.
Prior to his short-lived Birmingham reign, the ex-England striker had previously taken charge of Derby County and D.C. United, but his stint in charge of the former ended with the Rams suffering relegation from the Championship in the 2021-22 season.
Despite his underwhelming managerial CV, Plymouth - who are believed to have agreed a three-year contract with Rooney - said that the 38-year-old stood out as the "right candidate" during a round of interviews with several managers.
Rooney: 'Plymouth is the perfect next step for my career'
"Taking this role at Plymouth Argyle feels like the perfect next step in my career - and I would like to thank the Chairman and Board for the faith they have shown in me," Rooney told the official Plymouth Argyle website.
"This is an opportunity to be part of an exciting project. I look forward to helping to build a squad of players to play expansive football - and to entertain the Green Army. I have experienced first-hand how talented the existing group of players is here - and also the incredible atmosphere at Home Park.
"The club is on an exciting long-term journey, with a progressive plan in place. I am grateful for the opportunity to be part of it. I can't wait for the Championship season to start in August."
Chairman Simon Hallett added that he had full faith in the "passionate" and "intelligent" Rooney to bring exciting, attacking football to Home Park, adding: "Throughout the interview process, Wayne showed himself to be a passionate, intelligent, and knowledgeable candidate with an appetite to prove himself and develop his managerial career.
"So much so, that he reached out to the Board when we started this process and was attracted by the project at hand and showed a real plan on how to lead the football club forward.
Rooney to lead Plymouth in second Championship season
"His ambitions and aims match ours perfectly and we feel he is the perfect candidate to provide the exciting and attacking brand of football that we all like to see and help us achieve the club's mission. We look forward to another exciting season of Championship football, and I welcome him to Argyle."
Plymouth earned promotion to the Championship for the 2023-24 season under Steven Schumacher, but the 40-year-old left his position in January to join second-tier rivals Stoke City.
Argyle subsequently hired Ian Foster, who had previously served as Steven Gerrard's assistant with Saudi Pro League side Al Ettifaq, but he was only in charge for 17 games before being given the boot.
Director of football Neil Dewsnip took on the role of interim head coach for the remainder of the season, as Plymouth survived an immediate relegation back down to the second tier by the skin of their teeth.
The Greens accrued 51 points from their 46 matches to finish 21st in the division, just one clear of Rooney's demoted former team Birmingham, who went down alongside Rotherham United and Huddersfield Town.