The Lions fielded a total of six senior debutants and the hosts took advantage of that inexperience as Jack Lambert opened the scoring with just 10 minutes gone. He finished calmly after receiving the ball from Jarrett Rivers.
Jacob Gratton did have a chance for the visitors – his effort though was hit straight at Darlington goalkeeper Tommy Taylor.
The pressure the hosts were creating led to another goal just before the break. Jake Cassidy scored against his former side with a calm finish.
Any chance of a comeback ended immediately at the start of the second half when Gratton fouled Lambert and another ex-Lion scored – this time Will Hatfield from the spot.
The Lions did pull one back through Lewis Hey, when Gratton teed him up and he was left unmarked in the area to finish.
The three-goal lead was quickly reestablished for the home side though, when a corner found Jake Cooper who produced a powerful header that found the net.
Junior Mondal wrapped up the scoring after he rounded Declan Lambton and tapped in to make it 5-1 just before the end.
With moments to go it looked like Gratton had scored his first goal for the Lions, but it was ruled out for offside.
Guiseley will be hoping for a better result next time around when they travel to AFC Wimbledon in the first round of the FA Cup next Saturday.
After the match Guiseley assistant manager Paul Clayton said: “It has been a tough week, the lads will have gained some experience from that and they can learn from it.
“We showed some spirit, got a nice goal and now we just move on.”
Meanwhile, Farsley Celtic suffered a sixth straight away defeat despite taking a 20th-minute lead at Chorley when Lewis Turner volleyed in from Tyler Walton’s headed knockdown.
The home side went on to secure a 2-1 success following a deflected Billy Whitehouse strike and substitute Millenic Alli’s 88th-minute winner.
Neil Ross took charge of the Celtic team on Saturday following Adam Lakeland’s departure to join Curzon Ashton as their new manager.
Bradford Park Avenue were 3-0 down inside 10 minutes at Alfreton after Dayle Southwell, Yusifu Ceesay and Bailey Hobson netted goals.
Adam Nowakowski reduced the deficit from a Nicky Clee cross but Elliott Reeves and Conor Branson earned the hosts a 5-1 triumph.
Elsewhere, York City enjoyed their biggest-ever win under Steve Watson after seeing off Blyth Spartans 4-0.
Watson, who has been at the Minstermen helm since January 2019, watched his team inflict a sixth-straight defeat on struggling Blyth following goals by Paddy McLaughlin, Matty Brown, Mackenzie Heaney and Kurt Willoughby.
A long throw by Clayton Donaldson saw McLaughlin tap in to open the scoring in the second minute. Brown doubled the advantage with a clinical shot on the turn.
It was 3-0 when Heaney fired in after a Donaldson break down the left and, early in the second half, Olly Dyson ghosted past three Blyth players on the right before crossing for Willoughby to convert from close range.