North Ferriby were sunk by a 23rd-minute penalty from Dave Whittaker at Macclesfield Town despite being the better side for lengthy periods.
Macclesfield played for just over an hour with 10 men following the dismissal of John McCombe for a foul on Reece Thompson.
Goalkeeper Scott Flinders kept the home side in the game.
Ferriby started brightly and Flinders was out quickly to block Taron Hare before parrying a 25-yarder from Simon Russell.
The game was turned on its head after 23 minutes when Mark Gray was adjudged to have fouled Danny Rowe in the area and Whittaker sent Rory Watson the wrong way to score.
The sending-off of McCombe after 26 minutes did the Villagers no favours as Macclesfield regrouped and made life difficult.
Even so, Ferriby were unfortunate with Flinders producing another good save from Connor Oliver.
After the break, Rory Watson tipped over a shot from Whittaker before Oliver drew another fine save from Flinders and debutant Kyle Wootton curled a shot onto the bar.
Manager Steve Housham said: “I couldn’t fault the effort from the players. There were a lot of positives from the game.”
Macclesfield Town: Flinders, Halls, Byrne, Pilkington, McCombe, Holroyd, Rowe (Lewis 90), James, Norburn, Hancox, Whitaker (Sampson 90). Unused substitutes: Ross, Mackreth, Sutherland
North Ferriby United: Watson; Topliss, Gray, Middleton (Emerton 45) Skelton (Mukendi 78), Hare, Oliver, Russell, Fallowfield (Robinson 67), Wootton, Thompson. Unused substitutes: Armstrong, Kendall.
Referee: D Richardson (West Yorkshire).
Man of the match: Scott Flinders