The 30-year-old Belgium international has scored 15 goals and managed seven assists in 29 games this season, despite struggling with injury at the beginning of the campaign after the European Championships.
His league goal tally for the season was a career high. He also won the award in 2019-20, with team-mate Ruben Dias the recipient last season.
De Bruyne has also helped City to the brink of the title. They can secure their fourth Premier League trophy in five seasons if they defeat Aston Villa at the Etihad on Sunday.
The other nominees were City team-mate Joao Cancelo, West Ham’s Jarrod Bowen, Arsenal’s Bukayo Saka, Southampton midfielder James Ward-Prowse, Tottenham’s Son, and Liverpool pair Salah and Trent Alexander-Arnold.
Earlier on Saturday, De Bruyne’s City teammate Phil Foden was named as the Premier League’s Young Player of the Season.
“To win this award for a second time is an achievement that I am really proud of,” De Bruyne said.
“There is so much quality in the Premier League and it is a pleasure to be nominated with so many other great players who have had incredible seasons for their clubs.
“I think my performances this season have been good and I am happy that I have been able to contribute with goals and assists throughout the season.
“Thank you to all of the staff, coaches and especially my teammates because without them this wouldn’t be possible.”
(Photo: Marc Atkins/Getty Images)