The Seasiders had taken the lead through Andy Morrell, but goals from Michael Doyle, Mifsud and Robbie Simpson gave Coventry their first Championship win in five matches.
Coventry had started the first half slowly and the visitors' superior passing helped create the opening goal.
Stephen Hughes conceded a free-kick 35 yards out after a needless foul in the 32nd minute. David Fox whipped a teasing ball into the crowded Coventry box and former-Sky Blues favourite Morrell gently glanced a header past goalkeeper Andy Marshall.
Coventry looked weak going forward, but a spark of Maltese magic from Mifsud helped win a penalty in the 43rd minute.
The striker had raced past left-back Danny Coid on the right side of the area, only to be tripped. Referee Mike Thorpe pointed to the spot and Coventry captain Doyle coolly placed the ball into the top-right corner of Paul Rachubka's goal.
Coventry started the second half strongly and kept Blackpool on the back-foot for the entire period.
Early attempts from Doyle and Leon Best caused Blackpool concern, and right-back Shaun Barker nearly scored an own goal in the 66th minute from a Coventry corner.
But it was substitute Dele Adebola, who had entered play ten minutes earlier for Best, who crafted City's second goal with a slick throughball to Mifsud. The man they call 'mosquito' composed himself and fired the ball past Rachubka to grab his seventh goal of the season.
To add to Blackpool's woes, defender Kaspars Gorkss was given a straight red card for bringing down Adebola as the Nigerian raced towards goal.
And the away team's misery was complete when they failed to clear a messy corner and Robbie Simpson knocked the ball into the net five minutes from time to make it 3-1.