Julyan Collett brought Wanderers back down to earth with an equaliser, before Waitakere took control of the game in the first half.
Keegan Linderboom, who scored against Wanderers in the reverse fixture, had several shots on goal but was unable to put Waitakere ahead.
At halftime the teams were still locked at 1-1 with the result still to play for.
In the second half, Waitakere captain Jake Butler showed his experience beating two defenders but his shot fired just over the bar.
The defining moment for Wanderers came when Alex Frank, who won the youth league with Wanderers last season, was brought on to bring some added firepower up front.
In the 67th minute he was played in and made no mistake, putting Wanderers 2-1 up and in grasp of the team's first win in over a year.
A flurry of substitution followed as Wanderers looked to plug their defence with as many men as possible to hold on to their lead.
Nicolas Zambrano had one more attempt in the 88th minute to bring Waitakere level but it went over the bar before the referee ended the game.
The win still leaves Wanderers at the bottom of the table on six points, but it stopped them from creating a new record of 25 games without a win.
Club chairman Dave Douglas was more than proud at the result after the game, commenting to the fans that had stuck by the team during a difficult period.
"To all of our supporters and Blue Army faithful, that is for you," Douglas said.
"Thanks for always sticking by us, finally winners in blue."
The result had also received praise from fans in Papua New Guinea, who have been following Tommy Semmy's journey at the club.
"Well done to my countryman Tommy Semmy and the Wanderers boys, support all the way from PNG," David Heau Homoka said to the Hamilton Wanderers Facebook page.
The team sits six points behind the Wellington Phoenix Reserves in the spot above them, but have a chance to end a disappointing season with a flourish.
