Michael Higdon headed home his first goal at St Mirren Park midway through the first half of Tuesday night's quarter-final and Jack Ross added a deflected second just after the hour.
Motherwell had come from two down to draw in Paisley on Saturday but their comeback attempts ended when Stephen Craigan netted an 80th-minute own goal to make the final score 3-0.
St Mirren have now knocked Well out of a cup competition three times in five seasons and the defeat was Jim Gannon's first domestic loss on the road since taking over at Fir Park.
Gannon switched to a 3-4-3 formation with Shaun Hutchinson in for Ross Forbes as he looked for an improvement on the performance which needed a late Lukas Jutkiewicz double to rescue a point on Saturday.
His side made a positive start and Jim O'Brien saw a powerful 25-yard strike parried wide by Paul Gallacher.
But the visitors soon fell into the bad habits that hampered them at the weekend by conceding possession inside their own half.
Andy Dorman could not get enough power in his 20-yard strike after Hutchinson's throw had put Tom Hateley in trouble and John Ruddy's deflected clearance fell kindly for Well after Billy Mehmet had closed the goalkeeper down.
Motherwell again struggled to cope with Dorman's runs and one ultimately led to the opener.
Yassin Moutaouakil bundled over Dorman after being caught the wrong side and the midfielder's inswinging free-kick found Higdon 12 yards out.
Ruddy dived to get a hand to the header but the ball spun over the line as Higdon, who had come in for Tom Brighton after he ruptured a cruciate ligament during Saturday's 3-3 draw, celebrated his second goal in this season's competition.
Gallacher dived to hold Jamie Murphy's low strike from 20 yards as Motherwell tried to hit back immediately, but they struggled to break through an organised St Mirren side and the hosts continued to look dangerous on the break.
Gannon switched to a 4-4-2 at half-time, just as he had done when Motherwell trailed 1-0 on Saturday, with Bob McHugh and Chris Humphrey replacing Moutaouakil and Murphy.
Jutkiewicz had a great chance in the 54th minute when Hutchinson's long ball sent him clear but Gallacher came off his line to divert the striker's effort wide with his body.
Allan Johnston, making his first St Mirren start, headed wide under pressure from Mehmet's cross and the former Kilmarnock midfielder soon set up St Mirren's second in the 61st minute.
As Saints pinned Well back, Johnston laid the ball off for overlapping right-back Ross, whose drive took a deflection to fly inside Ruddy's near post.
Motherwell, roared on by a full away stand, stepped up their efforts and Coke had a shot deflected wide by John Potter after O'Brien fed his run into the box.
But the tie was put beyond Motherwell when Craigan turned into his own net after Dorman, now playing on the right, swept past Mark Reynolds and cut the ball across the face of goal.