Danny Ings' brace and a Lloyd Jones header made for a tight game at the home of Chester FC but Neil Critchley's side were ultimately edged out.
Critchley made four changes to the team that lost to Sparta Prague in midweek, with Rhian Brewster, Cameron Brannagan and Corey Whelan returning, the latter as captain.
The game started at a blistering pace, with each team registering a goal in the opening 10 minutes.
The Potters struck first, Tyrese Campbell pinching the ball just outside the area and forcing a save from Caoimhin Kelleher before Julien Ngoy followed in to tuck the rebound away.
However, Jones ensured the Reds were not long behind, meeting Harry Wilson's inswinging corner and powering a header home.
Brewster, Ings and Brannagan all subsequently tested the Stoke goalkeeper as the home side began to turn the screw in a bid to complete the turnaround.
The former pair combined beautifully to set Brewster up for a shot but Daniel Gyollai did well to save a powerful attempt and Ings’ subsequent effort.
And, moments later, Campbell put Stoke back in front, the forward picking up the ball down the Reds' right-hand side before squeezing an attempt under Kelleher.
Liverpool were unfortunate not make immediate amends when pinball in the Potters' box ended in Ings shooting over - but they were to suffer a further blow before the break.
With half-time fast approaching, Oliver Shenton collected the ball and hit an unstoppable effort into the top left corner to make it 3-1.
Liverpool were quick out of the blocks in the second period, with Brewster winning a penalty not long after the restart.
And though Wilson's initial effort was stopped, Ings followed in to net his first goal of the game and give the Reds hope of a second-half fightback.
Unfortunately, attempts to push for an equaliser left the hosts exposed, allowing Stoke to restore their two-goal advantage with 20 minutes left to play, Daniel Jarvis showing good feet to work space before cracking a shot in.
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Critchley called for Yan Dhanda, Juanma and Paulo Alves from the bench as he looked to change his side's fortunes as the game wore on.
That pressure began to tell, with Ings having a shot cleared off the line and Wilson was unfortunate to see an attempt cannon off the upright
But an injury-time penalty won by the latter and converted by the former was to prove but a late consolation as the Reds ended up on the wrong side of a thrilling contest.
Liverpool U23s: Kelleher, Whelan, Johnston (Dhanda), Jones, Masterson (Juanma), Brannagan, Kane, Ejaria (Alves), Ings, Wilson, Brewster.
Unused subs: Williams, Parker.