Jordan Thewlis' hat-trick ensured Town made it four consecutive away wins as Southport were beaten 4-1 at Haig Avenue.
Thewlis opened the scoring after just 30 seconds, converting Joe Leesley's pull back, and made it two on 18 minutes with an accurate header.
Gary Roberts' 55th minute penalty gave the hosts hope of a comeback, but Thewlis completed his hat-trick in the 73rd minute to put the result beyond doubt.
Leesley then capped another fantastic display with a goal as he powered a low drive through a host of bodies to make it four.
Simon Weaver made one enforced change from Saturday's 5-1 win at AFC Telford as Jake Wright was replaced by David Morgan who made his first start for the club.
The referee's whistle had barely left his lips before Town took the lead through Thewlis.
Morgan's ball over the top of the defence was chased down by Joe Leesley who won possession from a Port defender and showed great composure to square to Thewlis who was left with an easy finish.
Town were dominating the early proceedings and claimed their second goal of the game after 18 minutes as Thewlis guided a header back into the bottom left corner.
Thewlis almost claimed his hat-trick on the half hour mark, but could not stretch far enough to turn Leesley's low cross, that somehow evaded everyone waiting in the area, into the net.
With three minutes to go until half time, Jack Emmett had the chance to make it three, but Mark Halstead denied the one-on-one chance after the midfielder had latched onto Morgan's pass.
The hosts pulled a goal back ten minutes after the restart as Nathan Lowe's magnificent 40 yard effort was kept out by James Belshaw, but Town's stopper caught Ethan Jones following in looking for an easy tap in, resulting in a penalty kick.
Roberts stepped up and found the bottom left corner to hand The Sandgrounders a way back into the game.
Town looked to instantly restore their two goal advantage, but Leesley's shot was collected by Halstead moments before Falkingham curled just wide of the top right corner.
Ryan Fallowfield was the next to go close for Town, but saw his finish kept out by Halstead after running onto Thomson's lay off.
Town's third eventually came after 73 minutes as Leesley beat Jacques Kpohomouh and crossed for Thewlis to complete his hat-trick.
Leesley was next to get in on the goal scoring act as, after Thewlis' finish was cleared off the line, the winger powered a low drive through a host of bodies and in.
Harrogate Town: Belshaw, Fallowfield, Parker, Falkingham, Kennedy, Burrell, Thomson, Emmett (Burdett 82), Leesley, Thewlis, Morgan
Subs not used: Burdett, Cracknell, Middleton, Day, Gooda
Goals: Thewlis 1, 18, 73, Leesley 81
Booked: Belshaw, Parker
Southport: Halstead, Jackson, White, Jones (Merrie 53), Kpohomouh, Smith, Lowe, Schumacher (Fletcher 32), Roberts, Sampson, Jones (Sang 65)
Subs not used: Cockerline, Zama
Goals: Roberts 55(p)
Booked: Fletcher, Roberts
Referee: D McNamara