Here the PA media agency takes a look at five key talking points ahead of the game.
A long farewell?
O'Neill waited a long time for the right opportunity in club football, but though Stoke's offer finally tempted him away the 50-year-old said he could not just leave Northern Ireland in the lurch. The deal with the Potters will see him take charge not only for the final two qualifiers but also the play-offs in March in the likely event that Northern Ireland secure a place. The players want O'Neill to lead the side into Euro 2020 should they qualify, but the man himself has sounded more circumspect, aware of the demands of juggling both roles for too long. Either way, current play-off permutations suggest Saturday will be his final game in Belfast, and the Green and White Army will surely express their thanks for the considerable achievements of the last eight years.
The Northern Ireland players say they want to look no further than their final two Group C games but with automatic qualification high unlikely, attention will shift soon. As things stand, they would face a trip away to play Bosnia & Herzegovina, although that could change in the coming days as the final group games take place.
Hot reception for Koeman?
Holland manager Ronald Koeman may find himself an unpopular man with the Windsor Park faithful even before kick-off on Saturday. The former Southampton and Everton boss branded Northern Ireland's style "outrageous" and "terrible to watch" last month, provoking a forthright response from O'Neill, who was clear it was not his side's job to entertain their opposition. If the Northern Ireland manager is looking for a little extra motivation for his players, he might just slip it into his pre-match team talk.
Northern Ireland's 3-1 defeat to the Dutch in Rotterdam, which saw Koeman's side equalise in the 80th minute and score twice in stoppage time, was a crushing blow for O'Neill's side. However, they showed strong character by going to the Czech Republic four days later and securing a 3-2 win, having gone 3-0 up in the first half against a side high off a shock win over England a few days earlier. That performance, both the dominance of the first half and the dogged resistance of the second, will have restored some confidence to O'Neill's men for their final Group C games.
Can anyone stop Depay?
Northern Ireland did a good job of keeping Memphis Depay quiet for 80 minutes at De Kuip last month, but the last 10 were enough for the Lyon man to change the game. He scored twice, the equaliser and then the largely academic third, taking him to seven goals in his last 10 internationals, and is the clear dangerman in the Dutch attack.