Accies had hoped to secure only their second home win in the SPL this season but goals from Richie Foran and Adam Rooney sealed the points for the Highlanders, despite a strike from Simon Mensing, who later missed from the penalty spot.
Hamilton - who picked up their first win of the campaign at New Douglas Park just last week - finished with the lowest number of home wins in the top-flight since 1975.
Accies made two changes for the visit of Inverness. James Chambers and Lee Kilday were added to the team whose fate was sealed with defeat to St Johnstone midweek, with Mark McLaughlin suspended and Jon Routledge absent from the squad.
Caley Thistle made just one change, as Aaron Doran was named in the side ahead of the injured Chris Hogg.
Earlier in the day Hamilton announced that nine first team players, as well as coach Stuart Taylor, would be departing after day's game as they prepare for life in the Irn-Bru First Division next season.
One of those players, David Buchanan, carved out the first real chance of the game when his shot forced a decent save from goalkeeper Jonny Tuffey.
Accies were threatening again moments later when Nigel Hasselbaink's pass was collected by Chambers and he unleashed a ferocious shot that fell just wide of the target.
Chances had been few and far between and Inverness forward Rooney should have done better with a shot from 25 yards that dipped over the crossbar and failed to trouble Tomas Cerny in the Hamilton goal.
The game had an end of season feel about it but Caley Thistle managed to open the scoring a minute from the interval when Doran's cross found Foran at the back post and he nodded home from close range.
Dougie Imrie could have levelled just seconds later but he was denied the sight of the net bulging by Tuffey's impressive block.
Hamilton were back on level terms just five minutes after the restart when Gary McDonald's corner found Mensing in front of goal and he bulleted a header past Tuffey from close range.
But Inverness restored their lead eight minutes later when Nick Ross found Rooney in plenty of space and he calmly stroked into the back of the net from 15 yards.
Imrie was not too far away with a swerving effort from the edge of the box that fell narrowly past Tuffey's left-hand post as Accies tried to haul themselves back into the game once again.
Hamilton were handed a great chance to level the scoreline when Tuffey was judged to have tripped Imrie in the box and referee Iain Brines pointed to the spot with 72 minutes gone.
Mensing stepped up for the penalty but saw his shot crash off the crossbar, as he notched up his third spot-kick miss of the season.
The home side continued to press for an equaliser and Tuffey produced a great one-handed save to deny Imrie before Jim McAlister blasted over with the gaping net at his mercy, as Caley Thistle held on for the win.