Former Caley midfielder Imrie fired home a 30-yard strike after just 38 seconds in an explosive start.
The goal-of-the-season candidate proved decisive, inflicting a second consecutive home league defeat on Caley Thistle.
Hamilton manager Billy Reid made six changes to the team which lost 1-0 at Raith in the Co-operative Insurance Cup in midweek.
Teenage Dutch striker Nigel Hasselbaink - nephew of former Chelsea frontman Jimmy Floyd Hasselbaink - made his debut and was an impressive addition. Also into the team came Andrew Graham, David Buchanan, Kyle Wilkie, Jon Routledge and Grant Gillespie.
But it was Imrie - one of those who kept their place - who stunned his former employers with a superb early goal.
He stripped Lee Cox of possession before firing into the top corner beyond the reach of Ryan Esson.
Esson's inclusion was one of two changes made by Inverness to the side which beat Peterhead 3-0 on Wednesday, with full-back Kevin McCann also coming in - making it the same starting 11 who destroyed Dundee United 4-0 at Tannadice last Sunday.
Today's performance from Inverness paled in comparison to the show they gave against the Tangerines, with no shots on or off target from the hosts throughout the first half.
Hamilton looked comfortable in attack and defence and Marco Paixao would have doubled the visitors' advantage after 25 minutes but for the athleticism of Esson.
The Portuguese player tested the hosts' shot-stopper with a strike from the edge of the box after a lay-off from his twin brother Flavio.
Ross Tokely replaced McCann, who was struggling with a groin injury, to try to shore up the home defence which was being tested by Hasselbaink but was booked after 35 minutes for a foul on the 19-year-old Dutchman.
Goalscorer Imrie sent the subsequent 35-yard free-kick low and around the wall, inches wide of the post.
Hasselbaink broke quickly on the counter-attack five minutes after the interval to cut back to Flavio Paixao in the box, but his low shot was blocked by Kenny Gillet.
The rebound fell at the feet of Imrie, whose angled effort from inside the area went over the bar.
Inverness produced their first real chance after 55 minutes when Jonny Hayes played a clever free-kick short to Nick Ross who crossed into the box towards Eric Odhiambo, but his header was cleared at the cost of a corner which came to nothing.
On the hour Hamilton's Andrew Graham forced Esson to make a low block from a close-range header after he connected with a deep cross from Kyle Wilkie.
The test seemed to fire up Inverness and their top scorer Adam Rooney managed to lob goalkeeper Tomas Cerny but Graham was back in time to prevent a goal.
At the other end Hasselbaink then played in Flavio Paixao whose low shot was stopped by Esson.
Inverness manager Terry Butcher introduced attacker Shane Sutherland for teenager Nick Ross as his side pursued an equaliser, while Hamilton boss Reid swapped Hasselbaink for Joel Thomas.
Rooney might have levelled but steered the ball wide with only nine minutes remaining after running on to an Odhiambo through-ball, but he was spared his blushes for not hitting the target by being flagged offside.
Thomas then used pace and power to break free but hit the side-netting from an angle when just inside the box.
Graham looked as if he may have brought down Sutherland in the closing stages but referee John McKendrick waved away shouts for a last-minute penalty from the disgruntled home support.