Goals from Zurab Khizanishvili and Shefki Kuqi helped ten-man Rovers to their 13th home win of the season.
Mark Hughes made four changes to the side that secured sixth spot with a 1-0 win over Chelsea on Tuesday night.
Paul Dickov and Kuqi replaced the newly crowned Player of the Year Craig Bellamy and Florent Sinama Pongolle up front. Aaron Mokoena came in for Steven Reid at right-back, whilst Sergio Peter was handed his first Premiership start on the left.
Manchester City made two changes following Thursday night's defeat to Arsenal, with Sun Jihai and Albert Riera replaced by Sylvain Distin and Kiki Musampa.
The Ewood Park party was brought to an unfortunate silence on eight minutes when Mokoena was stretchered off.
Joey Barton had played a neat one-two with Darius Vassell before firing just wide under the challenge of the South African and Mokoena remained on the floor for almost five minutes, before being replaced by Brett Emerton.
Concern for the Rovers right-back and the persistent Blackburn rain led to an altogether disappointing opening half-hour, which was brought to life only momentarily by a streaker's lap of honour.
But on 35 minutes, Rovers were gifted the opening goal. David James dropped Peter's corner and Khizanishvili lifted the ball over the head of Claudio Reyna to make it 1-0.
Two minutes later and City were almost back level. Barton spotted the run of Musampa through the middle, but from just four yards out Brad Friedel produced a sensational one-handed reaction save from the Dutchman's point-blank volley.
The second half kicked off in blistering fashion and, just seven minutes in, the home side doubled their lead.
Emerton scampered into space down the right before delivering the perfect ball in across goal and Kuqi arrived to divert the ball past James for his eighth goal of the season.
Tempers frayed with captains Distin and Lucas Neill both picking up bookings, before midfield maestro Tugay was shown a straight red for a two-footed lunge on David Sommeil.
With just nine minutes remaining, Paul Gallagher made his first appearance this season, replacing Peter, and his impact was almost immediate. Stoke City's top scorer this season found David Bentley on the left and from his whipped ball in, Kuqi just failed to connect before Michael Gray put his diving header just wide of the post.