Inverness got off to a flier with Dougie Imrie netting after only 35 seconds for one of the quickest goals of the season.
Don Cowie broke down the right and Imrie timed his run to perfection to meet the cross and slam the ball home from eight yards.
Rory McAllister headed the second goal midway through the first half after Greg Fleming produced a fine reaction save to block a Marius Niculae header.
But Gretna refused to lie down and pulled a goal back four minutes later when Steven Hogg headed in a free-kick from Brendan McGill.
Niculae tried his luck from distance in a bid to restore Caley Thistle's two-goal lead, but his effort was wayward and Fleming was untroubled.
The Romanian came closer after being set up by McAllister at the edge of the area but he was just a foot wide.
Three minutes from the break, the lively Imrie shot narrowly wide with Gretna caught short at the back.
Barry Wilson made it 3-1 four minutes into the second half with a stunning strike with the outside of his right boot from 18 yards which left Fleming with no chance.
Caley Thistle went for the jugular after that. Imrie headed just wide after great work from Wilson and then Ian Black volleyed just past the post from a Cowie pass.
Gretna struggled to stay in touch but Gavin Skelton came close with a curling shot which flashed wide.
But Niculae should have made it 4-1 midway through the half but he hesitated in front of goal and Craig Barr made a last-gasp block.
The goal was only delayed a couple of minutes. Imrie this time turned provider to cut the ball back for Cowie, who slammed a low shot past Fleming.
Ross Tokely made it 5-1 when he headed in a corner from substitute Guy Kerr with two minutes left.
Substitute Iain Vigurs volleyed home number six in the final minute to complete Gretna's misery.