Mumbai rode on their best opening stand of the season - 93 runs -- provided by Sachin Tendulkar (48) and Dwayne Smith (47) and a quick-fire unbeaten 34 by Dinesh Karthik to rattle up 170 for six at the Wankhede Stadium.
The hosts then bowled out the visitors for 105 in 18.2 overs to emerge convincing winners and shoot to the second position on the league table with 16 points behind leaders Chennai Super Kings (18), whom they had beaten comprehensively on Sunday.
Only Manvinder Bisla (17) and Jacques Kallis (24) got the starts for the Knight Riders without flourishing fully among the top five batsmen after the dismissal of captain Gautam Gambhir for a duck.
Spinners Harbhajan Singh (3) and Pragyan Ojha (2) were the main wicket takers along with Mitchell Johnson (2) and Lasith Malinga (2) while Abu Nechim Ahmed too got a wicket.
It was Mumbai's sixth straight home win of the season and 8th overall.
The comprehensive defeat, their tenth in 12 games against Mumbai in the tournament's history, was also the Kinght Riders' 8th loss of the season and they are virtually out of contention for a berth in the four-team play-offs.
Knight Riders began the stiff run-chase disastrously when they lost their captain Gautam Gambhir for a second-ball duck in the first over from Mitchell Johnson.
Bisla and Kallis took the score to 38 at the end of the sixth over of power play, but then the former dropped on 0 was stumped while trying to give a charge to left-arm spinner Ojha who also removed Yusuf Pathan cheaply.
And when Kallis was out to Harbhajan for 24, it left the Knight Riders in a very difficult position at 58 for 4 just at the half way stage of their innings.