Pompey grabbed the lead on 11 minutes through the influential Svetoslav Todorov after a mishit cross was headed off the line and straight to the Bulgarian who volleyed home.
The Owls hauled themselves level on 27 minutes when Leon Knight raced onto a long ball to dink it over the hesitant Shaka Hislop.
But after the break, the visitors took control with Todorov adding to his tally with a neat finish past Kevin Pressman and substitute Gary O'Neil put the icing on the cake after good work from Todorov and Vincent Pericard.
Leicester City had briefly closed the gap at the top of the First Division after a 2-1 home triumph over Rotherham United.
The Foxes dominated proceedings at The Walkers Stadium but it was not until five minutes into the second half they made their superiority pay when Paul Dickov glanced home Alan Rogers's free-kick.
Jordan Stewart doubled the advantage when he rifled a shot into the top corner on 64 but Martin McIntosh's header two minutes later reduced the arrears.
An open game at Turf Moor remained deadlocked until Burnley defender Mark McGregor headed home a free-kick for his first goal of the season against high-flying Norwich.
The Canaries have never won at Turf Moor and The Clarets ensured that sequence continued when Glen Little grabbed a second on 85 minutes.
Nottingham Forest enjoyed the best of the first half at Molineux and grabbed the lead on the stroke of half-time through Marlon Harewood.
Two goals in four second half minutes turned the game on its head as Kenny Miller equalised (76) before Dean Sturridge (80) headed Wolves in front.
Reading moved into the play-off places with a hard-fought victory over rivals Watford. Neil Cox's first half penalty was saved by Royals keeper Marcus Hahnemann and on 61 minutes Kevin Watson's long range drive took a wicked deflection en route to the back of the net.
Sheffield United remain in the promotion hunt after a crushing victory at ten-man Bradford City. Debutant Steve Kabba put The Blades ahead on 14 and loan signing Dean Windass (40) returned to his old stamping ground to extend the visitors' advantage.
Gus Uhlenbeek was sent off for The Bantams early in the second half, and Shaun Murphy piled on the misery with a third goal just before the hour mark and Michael Brown's 80th minute penalty compounded the host's woes. There was even time for Carl Asaba to poach a fifth with two minutes remaining.
Ipswich were in control for prolonged periods at Portman Road after Darren Bent's tenth minute header put them in front.
But a mistake from Chris Makin enabled Coventry substitute John Eustace to haul the visitors level on 74 minutes only for Pablo Counago to pounce for the winner on 83 minutes.
Crystal Palace picked up a priceless win at home to Grimsby with Shaun Derry's (39) first of the season setting the ball rolling. Dele Adebola's second league goal of the campaign sealed the points.
Gillingham slipped to defeat at Walsall, with Junior's neat finish after a crisp move on seven minutes proving decisive.
Brighton's recent resurgence continued with a stunning fightback at Preston. Chris Lucketti and Richard Cresswell put the home side in the driving seat in the first half.
Simon Rodger handed Brighton a lifeline after the interval with a clinical volley and Steven Sidwell equalised on 72 minutes.
Stoke City crashed to an eight successive defeat as Steven Reid's second minute goal was sufficient to hand Millwall the points at The Britannia Stadium.
Click below for an individual match summary:
Bradford 0-5 Sheff Utd
Burnley 2-0 Norwich
Crystal Palace 2-0 Grimsby
Ipswich 2-1 Coventry
Leicester 2-1 Rotherham
Preston 2-2 Brighton
Reading 1-0 Watford
Sheff Wed 1-3 Portsmouth
Stoke 0-1 Millwall
Walsall 1-0 Gillingham
Wolverhampton 2-1 Nottm Forest
Click here for Division One table
