Wales Under-21 winger MacDonald opened his Swansea account in the 31st minute before clinching the win late on.
Swansea, despite naming a second-string outfit, dominated from start as League Two outfit Brentford were put to the sword by MacDonald's clinical double.
Swans boss Roberto Martinez sprung the changes with ten new faces included from the Swansea side which fell to an opening-day defeat at Charlton.
Brentford were pushed onto the back foot from the off and Jordi Gomez and Febian Brandy were off target with early efforts on goal.
It wasn't long before Swansea were celebrating the opening goal and it arrived through MacDonald.
Andrea Orlandi cut inside two Brentford defenders and when his cross fell to MacDonald it was fired past visiting goalkeeper Ben Hamer.
The Bees were fortunate to escape going further behind moments later when Gomez's long-range volley bounced back off the crossbar.
The second half continued to see the home side on top and only a fine reflex save from Hamer denied Spanish midfielder Gomez extending Swansea's lead.
Swansea suffered a blow when Fede Bessone was carried off with a rib injury on the hour-mark to force a reshuffle in the home defence.
But the injury didn't stop Swansea's flow as Owain Tudur-Jones headed narrowly wide.
Despite their supremacy, Brentford refused to lie down and Marvin Williams headed inches over the crossbar.
But it was the wake-up call Swansea needed as McDonald doubled Swansea's advantage in the 69th minute.
Jason Scotland's shot was deflected into the winger's path and he cut inside his man before firing home from an acute angle.
Sub Moses Ademola crashed a fierce drive against the post, but Marcus Bean was dismissed at the death for two bookable offences to compound the misery of the visitors.