Full-time score from The Den
Blackpool sub Nile Ranger reduced the arrears with a 71st-minute strike to set up a nervy finale, but The Lions stood firm and held on for three hard-fought points to the delight of The Den faithful.
McDonald, who last scored for The Lions in a 2-2 draw with Burnley last November, swept home a super opening goal after 33 minutes before Scott Malone gave The Lions a 2-0 cushion, adding a second six minutes into the second-half.
Scott McDonald picked the perfect time to score his first goal in 28 games as Millwall moved up to fifth in the Championship table with victory against basement boys Blackpool.
That lead was doubled within six minutes of the restart with another clinical finish by Malone. Good play by Edwards and Fuller on the right worked the ball to McDonald who had spotted Malone's storming forward run, picking him out with a sublime pass that the left-back thumped home from 12 yards.
The visitors also had a penalty appeal turned down just before the break when Alan Dunne tangled with Miller just inside the area, but referee Andy Woolmer waved play on and Millwall went in holding a precious one-goal advantage.
Those celebrations could have been cut short within a couple of minutes of taking the lead as Blackpool responded strongly. Andrea Orlandi blasted over the bar from Lundstram's corner and then both Delfouneso and Donervan Daniels had unsuccessful stabs at the ball from a teasing Orlandi cross.
McDonald's celebration - running the length of the pitch to share the moment with his family in the Hospitality Boxes - was as much an expression of joy as it was a release from the frustration of a 27 game stretch without a goal for The Lions.
However there was to be no denying the industrious McDonald the goal that his display so thoroughly deserved. A move practiced on the training ground was executed to perfection on the pitch when Powell threaded a super free-kick through to McDonald, who peeled away from his marker and dispatched a low shot beyond the desperate reach of Lewis.
Some neat control by McDonald saw the Millwall man weave his way past two challenges and hit a curling shot that was comfortably collected by keeper Lewis as the home side tried to find a way through.
The Lions had a lucky let-off on 23 minutes when John Lundstram caught the back-line napping and his diagonal ball picked out Delfouneso, who had ghosted into the danger zone, the unmarked forward thankfully glancing his header off target.
Edwards then turned provider at the other end, setting up his fellow full-back Malone with a fine delivery from the right, but the left-back diverted his first-time shot wide of the mark.
Blackpool had the ball in the back of the net three minutes later when Ishmael Miller stabbed home from close range, but the effort was ruled out for a foul by Nathan Delfouneso on Carlos Edwards in the build-up.
After a fairly subdued opening it was The Lions who created the first scoring opportunity on eight minutes. A delightful pass from Powell picked out Malone, who was promptly sent tumbling 35 yards out. Lee Martin's free-kick was curling towards the head of Ricardo Fuller, but visiting keeper Joe Lewis showed a strong pair of hands to punch clear under pressure from the striker.
Having lost their two previous outings at the Den, Millwall were determined to get back to winning ways and sign off for the international break on a high note.
Jimmy Abdou was missing altogether, having flown back to France on compassionate leave, whilst new loan signing Mathias Ranegie started on the bench.
As expected, manager Ollie made a number of changes to the team that faced Southampton in midweek - eight in all - with midfielder Jack Powell handed his first ever Championship start.
A third goal was not to be, but there will be few complaints from the home camp following a gutsy display that continues Millwall's impressive start to the season.
In fact Holloway's men could have finished with another goal to their credit deep in injury-time when a super touch from Ranegie picked out Gueye, who slipped the ball to Malone on the left flank. Malone drove forward before firing an angled drive across the face of goal and narrowly wide.
The tactical switch, sticking Webster to man mark Ranger, worked a treat and there was barely a peep out of the Blackpool man thereafter.
Blackpool's persistence certainly caused a few anxious moments for the home fans, and centre half Byron Webster was introduced in the final nine minutes to add an extra defensive body for Millwall in place of impressive debutant Powell.
At the other end a huge upfield punt by David Forde was so nearly converted by Ranegie, but the sub just lost control of the ball as he shaped to shoot.
It could have been 2-2 just two minutes later when Ranger skipped into the box and laid the ball off to fellow sub Davies, but he drove wastefully wide of the goal.
Within nine minutes of his introduction Ranger had handed the visitors a lifeline, reducing the arrears with a sweeping low shot from 16 yards following a quick counter-attack and final ball through by Francois Zoko.
Blackpool responded by bringing on striker Ranger for Delfouneso and then Steven Davies for Miller, with The Lions handing a debut to striker Ranegie who replaced Fuller. Millwall:
Forde; Edwards, Dunne, Beevers, Malone; Powell (Webster, 81mins), Williams; Woolford, McDonald, Martin (Gueye,78mins); Fuller (Ranegie, 61mins). Subs not used: Gerrar, Webster, Briggs, Easter, Gregory.
Fuller (34mins), Dunne (39mins), Ranegie (89mins) Bookings:
Lundstram (28mins), Davies (72mins), J. Oriol (83mins) Bookings:
Lewis, McMahon, Daniels, Clarke, J Oriol, Perkins, Lundstram (E. Oriol, 74mins) Orlandi, Zoko, Delfouneso (Ranger, 56mins), Miller (Davies, 65mins). Subs not used: Parish, Rentmeister, Cywka, Zenjov.