The winner came courtesy of winger Danny Thomas in the 76th minute when he was first to react with a low left-foot drive for his third goal of the season, after keeper Simon Brown had palmed a mis-directed header from centre-back John Mackie into the danger zone.
However, it was Simon Wiles who took the plaudits, delivering the telling cross which left Mackie confused after only one minute from his entrance on to the pitch.
Macclesfield had dominated the first half, hitting the woodwork twice. The first came courtesy of another mis-directed defensive error when right-back Ben Starosta deflected a Kevin McIntyre free-kick on to the inside of the upright.
The second came in the 42nd minute when Macc's young striker Gareth Evans saw a deflected drive crunch off the crossbar.
In between Brentford were unlucky not to be awarded a penalty when Macc keeper Tommy Lee could only parry a Sammy Moore shot into the path of Alan Connell, who appeared to be barged out of the way by Luke Dimech as he looked to slot home the rebound.
Macclesfield, however, were by far the better side with Levi Reid drilling a shot inches over the bar and Terry Dunfield forcing a fine save from Brown with a close-range snap volley.
After the goal Macclesfield got the ball in the back of the net again when Wiles cushioned a Thomas cross into the path of Evans, who stroked the ball home only for Wiles to be penalised for a push on his marker.
Evans again had a golden opportunity to seal the game at the death, but from 15 yards blasted over the bar.