The hosts had not lost in 10 games in all competitions since they last faced the Steelmen in September, when Motherwell romped to a 4-1 victory, but that run came to a comprehensive end following another impressive showing from Stuart McCall's men.
Michael Higdon headed the visitors in front with 18 minutes on the clock, before Jamie Murphy's finish made it 2-0 just three minutes later.
The hosts grabbed a goal back just after the restart when Richie Foran clipped the ball home from close range, but Well restored their two-goal advantage five minutes later when Adam Cummins smashed home from inside the six-yard box.
The visitors then ended the match as a contest when Nicky law squared the ball for Henrik Ojamaa (72) to tap home, before sub Omar Daley made it 5-1 when his long-range effort squirmed under keeper Antonio Reguero.
A lacklustre Caley Thistle slipped to seventh in the table following the defeat, despite reclaiming the mantle as the league's top scorers.
Shaun Hutchinson replaced Simon Ramsden in the visitors' only change to the side which drew 1-1 at home to Dundee last time out.
Caley Thistle also made just the one alteration to the side which drew 1-1 at home to Hearts last Saturday with Gavin Morrison in for Philip Roberts.
Inverness started well with Aaron Doran finding Morrison whose shot from outside the area was saved by Darren Randolph.
Billy McKay fired wide for Inverness from the edge of the box as the hosts continued to push forward.
Motherwell absorbed the pressure and scored on their first meaningful attack as Higdon headed Nicky Law's cross past keeper Antonio Reguero from six yards.
Motherwell doubled their lead four minutes later when Murphy volleyed home.
He blasted past Reguero following a weak defensive header from Josh Meekings who tried to clear Chris Humphrey's cross.
Moments later it might have been 3-0 but Murphy hit the crossbar.
Reguero produced an excellent save to thwart Humphrey after Ojamaa failed to connect with a dangerous low cross from Steven Hammell.
The Spanish shot-stopper was swiftly called into action again when he pushed away another Murphy effort.
Owain Tudur Jones tried to turn the tide with a low 30-yard free-kick but Randolph was equal to it and Motherwell remained in the ascendancy.
Murphy forced another save from Reguero and Law shot inches over just before the interval.
Caley Thistle produced a response immediately after the restart when Foran reduced arrears.
The Irishman was found in the box by David Raven in the 48th minute and he neatly slotted his shot past Randolph from six yards.
But Motherwell restored their lead four minutes later when Cummins volleyed home a Tom Hateley cross from close range.
They added a fourth when Law played a one-two with Murphy before finding Ojamaa whose low angled shot from 10 yards beat Reguero.
It was the Estonian's first goal in 20 games.
Inverness did not give in and might have pulled one back when Doran hit the crossbar before Andrew Shinnie had a shot deflected over.
Motherwell continued to hunt more goals with Higdon denied by Reguero.
A fifth arrived with one minute remaining when Reguero fumbled a low 20-yard shot from Daley into the net.