Hiram Boateng was a 62nd-minute substitute as Cambridge United climbed to top of the Sky Bet League Two table.
A first-half brace from the spot from Paul Mullin set Mark Bonner's side on course for victory at The Sands Venue Stadium.
Tyler Cordner then scored an own goal before Joe Ironside put the game to bed with two goals in the final half-an-hour.
Boateng replaced Paul Digby with 28-minutes left of the clash - he's next in action on Tuesday night as Cambridge face Port Vale.
Biggleswade were not in action this past Saturday, while Sam Nombe wasn't named in Luton Town's squad as they fell to a 2-0 defeat against Stoke City.