Michael Beale fielded a strong team, including Danny Ings, Ben Woodburn and newly-appointed captain Harry Wilson, but they were second best to the young Saints.
Josh Sims gave the visitors a 13th minute lead, converting Yan Valery’s cross from the right, before Jake Hesketh’s long-range strike doubled the lead five minutes later.
Danny Ings’ converted Harry Wilson’s through ball to bring the Reds back into it on 35 minutes, but Olufela Oloma restored Southampton’s two-goal lead seven minutes after the restart.
Oloma then sealed the win with his second goal of the game midway through the second half, finding the top corner with a beautiful first-time finish.
Beale’s U23s will hope for a better performance when they visit Chelsea next Monday night, but first, they will face Danish side Odense in a friendly on Wednesday.
Liverpool XI: Grabara, Randall, Hart, Brewitt, Maguire, Williams, Wilson, Virtue, Ings, Woodburn, Phillips. Subs: Firth, Whelan, Kane, Gomes, Lennon.
Southampton XI: Lewis, Vallery, Wood, O’Connor, Cook, Jones, Olomola, Gape, Barnes, Hesketh, Sims. Subs: Bakery, Parkes, Willard, Rowthorn, Johnson.