The midfielder scored the only goal of a low key first half in the 21st minute before teenage striker Callum McManaman grabbed his first for the Latics 11 minutes after the break.
The game really came to life in the final quarter of an hour as substitute Nick Barmby netted either side of Diame's second but there was not to be a final twist as the visitors held on.
The sides were meeting each other in the third round of the FA Cup for the second successive season, with Wigan hoping for a repeat of last year's 4-1 victory at the DW Stadium.
Hull have endured a miserable 12 months since then, with relegation from the Premier League compounded by financial problems that took the club to the brink of administration.
But last month's takeover by local businessmen Assem and Ehab Allam has steadied the ship and results on the pitch have picked up, too.
Wigan's priority is undoubtedly trying to avoid following Hull into the second tier, and that was reflected by boss Roberto Martinez's team selection, which showed eight changes from their 1-1 draw with Bolton in midweek.
However, it was the visitors who enjoyed the better of the early stages, with forgotten midfielder Daniel De Ridder proving the biggest threat.
The Dutchman was making his first appearance for Wigan since May 2009 having returned to the club from Hapoel Tel Aviv in the summer, and twice he drew good early saves from Matt Duke.
First a flick-on from Jordi Gomez's corner almost caught the Hull keeper out before De Ridder let fly from 20 yards with a fierce effort that Duke had to beat away.
The 26-year-old then curled another shot wide after a lovely through ball from McManaman, so it was no surprise to see him heavily involved when the visitors deservedly took the lead in the 21st minute.
McManaman's ball in from the right broke for Diame and, although his touch was too heavy, De Ridder reacted first to stab the ball goalwards, leaving Diame with the simplest of finishes as Duke scrambled in vain.
Hull had offered next to nothing in attack but they probably should have been level in the 37th minute when new signing Matty Fryatt found space 18 yards out only to plant his lob just the wrong side of the bar.
Three minutes into the second half, Wigan came close to doubling their lead, and it was that man De Ridder at the heart of the action again.
His effort from the left of the area bounced back into play off Duke's near post and straight to McManaman, who could only head into the arms of the keeper with the goal gaping.
Martinez had challenged his fringe players to take their chance today and there was no doubt 19-year-old McManaman was determined to do just that.
He had looked lively all match and in the 56th minute he grabbed his first Wigan goal in style, cutting in from the left and curling an 18-yard effort beyond Duke and into the far corner.
Both teams were rather going through the motions but De Ridder came within a whisker of grabbing the goal he deserved with another fine effort only for Duke to tip the ball over the bar.
From the corner, McManaman scuffed a shot into the arms of Duke, while, at the other end, Al Habsi made his first real save of the match with a smart block to deny Fryatt.
And that proved to be a taste of things to come as, with 16 minutes remaining, Hull pulled a goal back. A lovely deep cross from Andy Dawson picked out 36-year-old substitute Barmby, who guided the ball into the far corner.
If the Tigers were dreaming of a comeback, though, their hopes were surely snuffed out three minutes later as Diame, who had only scored for Wigan once before, found space on the left before neatly clipping a shot over Duke.
Suddenly chances were coming thick and fast, with substitute Jamie Devitt drawing a good save from Al Habsi before, at the other end, De Ridder continued his battle with Duke.
Still Hull kept pushing and Barmby headed in his second from Devitt's cross with the game entering four minutes of stoppage time, but that was as good as it got for the Tigers.