Preston gained their second 1-0 win in four days on a cold afternoon watched by 13,801.
The win was Preston's first against Wimbledon since April 3 1982 and left struggling Wimbledon firmly at the bottom of Division One.
The winning goal came after 29 minutes by Preston's leading goalscorer and Jamaican international Ricardo Fuller, his seventh goal of the season.
After eight minutes, 34-year-old Dean Holdsworth on the right, outside the box had a shot that went wide of the left-hand post.
Preston's Paul McKenna hit a free-kick from outside the penalty box on the right which also went wide of the left-hand post after 20 minutes.
The dangerous Holdsworth had another chance in the box and his close-range left-foot shot was saved by Man of the Match Jonathan Gould who dived low at his right-hand post to save one-handed.
Wimbledon's Darren Holloway dragged down Fuller just outside the penalty box after 28 minutes and was shown the red card by the referee.
Graham Alexander took the free- kick straight away and it led to a Michael Keane shot from close range which Paul Heald, the Wimbledon keeper, could only parry and the ball went straight to Fuller, who followed it in from close range.
Wimbledon manager Stuart Murdoch had to withdraw Michael Gordon and bring on Malvin Kamara and Adam Nowland had a free-kick that Gould saved when he dived left to push the ball for a corner.
The fourth official signalled two minutes, but it was 1-0 to Preston at half time.
Brian O'Neil, who had a groin injury, was substituted by Richard Cresswell who is recovering from a hamstring problem.
In the 65th minute, Holdsworth again had a swivel shot in the box which went straight at Gould.
Wayne Gray came on for five-goal Wimbledon leading goalscorer Patrick Agyemang and Nigel Reo-Coker was booked for a foul on McKenna.
There then followed a series of substitutions by the managers and late on Eddie Lewis had a volley which Heald pushed away for a corner and with two minutes to go Kamara was booked for a foul on Lewis.