MacKinnon opened the scoring for the home side after 16 minutes and there was no reply from Saints, who came closest when Steven Anderson was denied by the woodwork in the second half.
Accies lost their opening game of the season against Inverness but have since bounced back with back to back wins over St Mirren and St Johnstone.
Saints were able to name Dave Mackay in the starting line-up after they lodged an appeal against the skipper's red card against Celtic midweek.
Boss Tommy Wright also handed a first start to on-loan Yeovil forward Adam Morgan for the trip to New Douglas Park.
Accies were sweating over the fitness of Tony Andreu and he started on the bench.
There was a late change to the team-sheet, however, when player-boss Alex Neil felt an earlier knock during the warm-up and replaced himself with Stephen Hendrie ahead of kick-off.
Despite the late alteration to the line-up, it was the home side who surged into the lead with 16 minutes on the clock.
Ali Crawford found Mickael Antoine-Curier out on the right and he cut-back for MacKinnon.
It was hardly a powerful shot but it was enough to beat goalkeeper Alan Mannus, who got a hand to the effort but was unable to keep it out.
Accies could have doubled their lead when Crawford decided to have a go himself with a ferocious effort from the edge of the box but Mannus was up to the task this time with a decent save.
The home side continued to press for a second goal and only some last-gasp defending from Saints prevented them from hitting the target.
Hendrie unleashed an angled drive from the left that looked set to leave the net bulging but Anderson managed to hook off the line.
The visitors were dealt a further blow when Michael O'Halloran was forced out of the action five minutes before the break.
He had suffered a knock earlier in the game and hobbled off to be replaced by Lee Croft.
Saints could have been back on level terms a minute after the restart when Michael McGovern misjudged the situation and came well out of his goal to claim the ball.
But Croft found himself in possession and was able to round the goalkeeper before floating the ball into the box, where Hendrie was able to intercept and clear the danger.
The Perth side continued to push for the leveller and only the woodwork prevented them from drawing level when Anderson saw his effort crash off the crossbar.
Accies also looked capable of finding the back of the net again and Crawford's corner found Martin Canning and he was only denied his moment of glory when his header was cleared off the line by Steven MacLean.
Despite a late push for a point by the visitors, Hamilton were able to hold on for all three points and notch up their second win this week.