Goals from Robbie Muirhead and Sammy Clingan in either half secured the three points against 10 man Well.
The reverse at Rugby Park was Motherwell's third league defeat in a row.
Motherwell handed Henrik Ojamaa his first start since his return to the club for a crunch meeting with Killie as they attempted to steer their season back on track.
The Estonian forward came off the bench for the second half of last week's defeat to Inverness and was added to the team for the visit to Rugby Park.
Killie were missing both Michael Ngoo and Craig Slater from the matchday squad.
Despite missing key personnel, it was the home side who made a storming start to the game.
Muirhead had passed up a glorious chance in the opening stages, but, with just nine minutes on the clock, he made amends by grabbing the opener.
He collected the ball from Chris Chantler before letting fly with an unstoppable shot from the edge of the area that had Dan Twardzik well beaten.
However, the Motherwell goalkeeper came to the rescue when he found himself one on one with Josh Magennis and raced off his line to block.
The Northern Irishman was thwarted again seconds later when his shot from distance was smothered by Twardzik as the home side heaped on the pressure.
Magennis then attempted to turn provider, nodding into the path of Muirhead 18 yards out, but his volley dipped just over the crossbar and he was denied his second goal of the day.
As the match raced towards half-time, there was no let-up from relentless Kilmarnock.
This time, Rory McKenzie had a go with a 25-yard drive that a full-stretch Twardzik just managed to turn past a post.
Chances for Motherwell were scarce, but Ojamaa saw an angled drive clawed away by Craig Samson, with Craig Reid unable to get a clean shot from the rebound.
Motherwell stepped up attempts at a fight back after the break, but a curling effort from the fit-again Iain Vigurs did little to trouble Sampson in the Killie goal.
There appeared to be no way back for Well when they found themselves down to 10 men.
Fraser Kerr was shown a straight red card for a high kick on Jamie Hamill on 76 minutes.
Two minutes later, Clingan stepped up to smash home the resulting free-kick from just outside the area and seal the points.