Stephen Robinson - who was already missing central defender and captain Peter Hartley through injury - was forced into three changes before the 28-minute mark after Charles Dunne and Carl McHugh clashed heads and then substitute Christian Mbulu suffered an eye injury.
There was more woe to follow for the hosts in the 40th minute when Jordan Jones netted as what appeared to be an attempted cross curled over the head of goalkeeper Mark Gillespie and inside the far post.
The home side were already struggling to get back in the game before Main was sent off in the 71st minute after receiving two yellow cards in the space of two seconds - one for fouling Stephen O’Donnell and another for immediately pushing him over.
The game was little over 10 minutes old when McHugh ran from behind Dunne to go for the same header and clattered into his team-mate. Dunne lay motionless on the turf before being carried off on a stretcher after a long delay and McHugh - who spent almost five months out with concussion two years ago - could not continue either.
Mbulu and midfielder Gael Bigirimana came on but Motherwell soon found themselves temporarily down to nine men. Main went down with a facial injury after the hosts defended a series of corners, and Mbulu walked off after experiencing problems with his sight.
Only Main came back on and midfielder Liam Grimshaw joined him from the bench to play at right-back, while Richard Tait moved inside to partner Tom Aldred as Robinson switched from a three-man central defence to a flat back four.
Killie took the game to the makeshift home defence and Greg Stewart, Jones and O’Donnell were all off target before the winger found the net as he lofted the ball from the left flank into the penalty area. Jones’ subsequent laughter suggested the outcome was unintentional.
Kris Boyd soon came close with an attempted chip before Motherwell had a chance during seven minutes of stoppage time when Danny Johnson set up Elliott Frear on the edge of the six-yard the box. O’Donnell snuffed out the danger with a diving block.
Jones hit the top of the bar during a counter-attack as Killie blocked the way to their goal after the break and Main’s frustration boiled over with his double offence.
Rory McKenzie and O’Donnell passed up half-chances to earn Kilmarnock a cushion and Motherwell twice threatened an unlikely equaliser. Aldred headed wide and Bigirimana volleyed beyond the far post before Killie sub Eamonn Brophy missed a glorious chance in the final seconds.