Ryan Hardie and George Cooper ensured Plymouth would claim all three points on a tough afternoon for the Silkmen on the south coast.
Hardie opened the scoring just past the half hour mark, as he latched onto a long diagonal pass before guiding the ball over the onrushing Jonathan Mitchell and into the net.
George Cooper would add two more in the second half, as Plymouth imposed themselves on the game following a host of Silkmen opportunities.
The Silkmen players could not be accused of a lack of fight, however, as they created numerous openings against one of the league's strongest sides.
Joe Ironside was denied a leveller moments before Plymouth's second by some desperate Argyle defending, whilst Shilow Tracey had come close to restoring parity moments after the Pilgrims' opener.
In a first half filled with chances for both sides, Theo Archibald looked lively early on – his corner forcing Palmer to readjust as the ball span goalward inside the opening minutes.
Joe Ironside would come close moments later, but he couldn’t quite connect with the ball after some good work from Danny Whitehead inside the Plymouth penalty area.
The Pilgrims would respond to this early pressure by putting the ball into the Silkmen goal just shy of the ten-minute mark; but Ryan Hardie quite clearly handled the ball in the build-up and the resulting strike was chalked off.
Macc would press for the opener once again through Ironside, whose looping header clipped the post on its way behind; with Argyle goalkeeper Palmer little more than a spectator as Macc, for a moment, looked set to open the scoring.
Plymouth would react to this scare by creating their best chance of the half up to that point, with Tyreeq Bakinson heading over from close range after an inch perfect cross from Danny Mayor.
Shilow Tracy would then run at the Pilgrims’ backline before trying to slip a ball through to Ironside.
His pass would be intercepted, but the Plymouth defender scuffed his attempted clearance and the ball bobbled just wide of Palmer's goal.
Ironside would be presented with another opportunity to open the scoring, but Palmer smothered the ball at his feet as he looked to divert the ball goalward.
Then came the opener. Hardie connected with a long ball over the top before flicking the ball over Mitchell and into the net.
Tracey almost pulled one back straight away, but he couldn’t find the required finish after a poor Argyle backpass presented him with an unexpected one-on-one opportunity.
Despite Macc starting the opening minutes of the second half on the front foot, Plymouth would force Mitchell into an inspired save ten minutes into the second period; with the Derby loanee clawing the ball to safety as the Pilgrims looked set to double their advantage.
Luke Jephcott struck the post moments later, before Joe Ironside was denied an equaliser by some last-ditch Argyle defending on the goal line.
Just two minutes later, Plymouth would find themselves two ahead.
George Cooper lashed a close-range effort past Mitchell after being picked out by Danny Mayor.
Cooper would add a third with little over ten minutes to play, finding the net from distance with a powerful drive.
The hosts risked little going forward after this, instead opting to see out the remaining minutes by frustrating the Silkmen - who were pushing to reduce the deficit right up until the final minute.
Attendance: 12,310 (111 away).
Macclesfield Town Line-Up: Mitchell, McCourt, Kelleher, Ironside (Blyth, 82’), Archibald, Kirby (Stephens, 76’), Horsfall, O’Keeffe, Whitehead, Tracey (Wilson, 80’), Fitzpatrick.
Unused Substitutes: Hamblin, Tollitt, Cameron.