Two goals from substitute Smalling have given Manchester United a half-time lead against a Burnley side that have threatened on several occasions at Old Trafford.
The Clarets almost made a dream start when ex-United player Michael Keane managed to lose Phil Jones, but headed a corner wide from close range.
Jones was soon forced off through injury to be replaced by Smalling, and the substitute wasted no time in making an impact for the Red Devils.
With his first touch, the defender rose highest to head the ball past Tom Heaton to give Louis van Gaal's men a sixth-minute lead.
However, Burnley were unbowed despite falling behind as Kieran Trippier delivered a pinpoint cross for Danny Ings to score his fifth goal in six games and stun Old Trafford.
Ings threatened again on 16 minutes, but saw his shot blocked by Marcos Rojo as the hosts struggled to impose themselves on proceedings.
Trippier continued to cause United problems from wide areas as he found Ings before the forward teed up Ashley Barnes, who curled his effort wide of David de Gea's goal.
Barnes again went close as another he met another precise Trippier delivery, but could only head over the bar.
United's first half didn't improve as Daley Blind was withdrawn after trying to play on, but with the break approaching, Smalling popped up with another header the give the hosts the lead.