Despite taking an early lead Southport left Nethermoor disappointed with the home side running out 4-2 winners.
There was no indication of what was to come when George Newell headed home after a deep cross from Jack Doyle found him unmarked at the far post. Frantic Guiseley appeals for offside were waved away by the officials and the goal stood.
Southport had a couple of chances to increase the lead before Guiseley levelled on 20 minutes after sloppy defending gifted the home side the equaliser.
Dan Hanford ensured the scores were level at half time with a couple of great saves before Adam Anson went close to seeing Southport go in to the break ahead with a fine bit of skill and turn but his shot flashed narrowly wide.
1-1 at half time was a fair reflection of the first period.
It all changed in the second half with the home side dominating the game and after they took the lead on 50 minutes there really looked like one result was possible.
It was a surprise that it took until the 80th minute before the lead was stretched to 3-1.
Southport did create a good opening with Carver going close but easily saved by the ‘keeper.
A rather soft penalty in the 89th minute was the final nail in the coffin with Guiseley converting to make it 4-1.
Southport did get one goal back deep into added time when a cleverly taken quick free kick by David Morgan was played to Matty Challoner and Marcus Carver was on hand to slot home.
No way back though with too little too late and it finished Guiseley 4 Southport 2.
Line Up; Hanford, Oliver (Antwi 67), Anson, Bainbridge, Challoner, Doyle, Benjamin, Morgan, Woods(Watson 79), Newell (Archer 67), Carver
Unused Subs: Ali & Vassallo.