The match got off to a disastrous start for the Lions, as the hosts scored twice in the opening ten minutes.
Shane Henry grabbed both the goals. First, he was found at the back post and scored with a free header, then minutes later the same player saw his shot from the edge of the area take a deflection and go past Marcus Dewhurst.
While the hosts dominated the start of the game, Guiseley got a goal back with just under half-an-hour gone, as a Kaine Felix cross eventually fell to Scott Garner who powered his effort into the right-hand corner of the goal.
Just before half-time, Felix nearly equalised, but his powerful, low drive was turned over by Matt Gould.
The hosts scored with their next attack as defender Rob Ramshaw made it 3-1 with a header after Glen Taylor had done well to deliver a good cross.
In the second-half, the Lions tried to get back into the match early on, when substitute Will Hatfield burst through on goal but James Curtis made a crucial interception.
Hatfield pulled one back though, with a superb free-kick from 30 yards out, that flew into the top corner. In added time, Guiseley nearly got the leveller, when Andy Halls saw his shot hit the crossbar.
Guiseley, who remain six points above the final relegation place, next face one of their longest away trips of the season as they face another side battling for a play-off place in Brackley Town.
After the match, Guiseley joint-manager Russ O’Neill, said: “We knew this was going to be a tough game, facing a side who are challenging at this point of the season.
“We wanted to take what we did against Curzon and the second-half against York and use it for this match, we didn’t start well, we got into the game and just couldn’t get that vital equaliser.”
Spennymoor Town: Gould, Henry, Curtis, Atkinson, Williams, Ramshaw, Chandler, Hall, Hawkins, Diamond (Boyes 76), Taylor. Subs: Elliott, Hibbs, Thackray, Harrison.
Guiseley: Dewhurst, Cantrill, Moyo, Garner, Halls, Langley, Purver (Fowler 61), James, Felix (Morrison 82), Barkers (Hatfield 45), Odejayi. Subs: Dyche, Digie.
Referee: James Bell