The visitors were arguably the better side before the break, only for Michael Smith to haunt his former club by breaking the deadlock.
Marcus Harness levelled quicky after the break and suddenly the Blues sensed they could claim all three points.
Their hope did not last long, however, as the Millers netted three times in the space of seven minutes to put the result beyond doubt.
Smith was handed his second goal of the afternoon on a plate, with Richard Wood and Ben Wiles soon piling on the misery.
Danny Cowley made one change from the side that thrashed Sunderland on home soil a fortnight earlier.
Defender Connor Ogilvie came in for his first appearance in more than a month after picking up a quad injury.
He replaced the suspended Ronan Curtis in a three-man back-line, while Shaun Williams returned to the midfield.
Meanwhile, injured Pompey skipper Clark Robertson – who used to play for the Millers – was sat with the travelling fans.
It was the visitors who made the brighter start and they enjoyed more possession and greater territorial advantage in the opening stages.
Williams had an early chance with a fierce long-range effort that kept awkwardly and was just about diverted over by Viktor Johansson.
There were plenty of forays forward from the Blues and balls into the box that were either intercepted or would not quite land right.
Michael Ihiekwe did particularly well to prevent a cross from Harness finding John Marquis in the centre.
Rotherham had offered little, but almost took the lead on 17 minutes when a Dan Barlaser free-kick was headed on by Ihiekwe.
It looked like being a simple finish for Rarmani Edmonds-Green at the back post, only for Gavin Bazunu to somehow claw the ball away.
Pompey, meanwhile, were showcasing plenty of energy, without being able to penetrate their opponents’ back-line.
And the hosts made them pay on 29 minutes, as Smith was left unmarked to head home a fine Wes Harding cross.
There was a quick chance to level when Williams was fouled just outside the box, but Harness curled the free-kick wide.
And Johansson did well to clear the danger before Marquis could charge him down just before the break.
Rotherham United 1
Cowley’s message at the interval seemed to do the trick, as Pompey were level within five minutes of the restart.
Joe Morrell can take some of the credit, making a well-timed sliding challenge to halt a dangerous Will Grigg surge.
And the visitors went up the other end to score, with HARNESS collecting a pass from Ryan Tunnicliffe and arrowing a shot into the bottom corner from the edge of the box.
But just as they started to get on top in the contest once again, the Millers were gifted back their advantage.
A shot from Ollie Rathbone flew straight at Bazunu, but the keeper failed to hold on and Smith capitalised.
His initial attempt was brilliantly blocked by Kieron Freeman, only for the loose ball to fall back to the striker, who found the net with a neat back-heel.
And Rotherham went further ahead on the hour mark, with nobody picking up Wood as he raced in to head home a Barlaser free-kick.
Pompey had collapsed and it soon got even worse, as Wiles collected Mickel Miller’s pass, turned neatly and fired in a fourth goal for the hosts.
Bazunu then managed to stop the rot by diving to his right and pushing behind a fierce free-kick from Barlaser.
Cowley tried to freshen things up by making a substitution on 70 minutes, as George Hirst came on to face his former club in place of Marquis.
And two more quickly followed, with Reeco Hackett and Louis Thompson replacing Tunnicliffe and Williams.
Bazunu then had to be at his best to keep out another Barlaser free-kick, courtesy of an acrobatic dive to his right.
Rotherham then saw out the final few moments with relative ease to ensure the Blues would make the long trip home on the back of a heavy defeat.
Rotherham (3-1-4-2): Johansson; Edmonds-Green, Wood (c), Ihiekwe (Ogbene 54); Barlaser; Harding, Rathbone, Wiles, Miller; Smith (Kayode 81), Grigg (Ladapo 68)
Goals: Smith 29, 55, Wood 60, Wiles 62
Booked: Ihiekwe, Rathbone
Subs not used: Vickers, Ferguson, Odoffin, Sadlier
Pompey (3-4-1-2): Bazunu; Freeman, Raggett, Ogilvie; Romeo, Morrell, Williams (Thompson 73), Brown (c); Tunnicliffe (Hackett 72); Harness, Marquis (Hirst 70)
Goals: Harness 49
Booked: Romeo, Freeman
Subs not used: Bass, Jacobs, Azeez, Gassan
Referee: Anthony Backhouse
Attendance: 9,684 (1,242 Pompey fans)