Slot's side welcomed their Championship counterparts to the AXA Training Centre for the behind-closed-doors clash, where Robbie Brady struck the only goal of the game for the visitors.
While the Reds were still without several of their Euro 2024 and Copa America stars, including Alisson Becker, Virgil van Dijk, Darwin Nunez and Cody Gakpo, no fewer than 25 players earned minutes under Slot in the narrow defeat.
Mohamed Salah and Dominik Szoboszlai were both named in the first XI, as were Jarell Quansah, Harvey Elliott, Kostas Tsimikas, Curtis Jones and Ben Doak, back from his serious knee injury.
Doak and Salah joined Fabio Carvalho in the front three for the first 45 in Kirkby, but the Reds fell behind just before the 30-minute mark, as Brady fired in a terrific long-range strike after Liverpool were caught out when trying to play out from the back.
Szoboszlai then made way for Wataru Endo with 33 minutes on the clock, and the Japan international was the only player to complete for the first half who also emerged for the second period.
The likes of Tyler Morton, Stefan Bajcetic, Kaide Gordon, Lewis Koumas and out-of-favour defender Nat Phillips were among 10 players introduced for the second period, where Trey Nyoni also replaced Endo on the 75-minute mark.
Liverpool pushed for an equaliser as the second half progressed, but Preston dug deep defensively to hand Slot his first unofficial defeat as Liverpool boss, albeit one that he will not be losing sleep over.
As well as Liverpool's batch of internationals, second-choice goalkeeper Caoimhin Kelleher was not involved in Friday's friendly, as Vitezslav Jaros and Harvey Davies shared the gloves.
The Republic of Ireland international is thought to be keen on a transfer elsewhere in search of regular game time, while young attacker Jayden Danns was nowhere to be seen either.
What next for Liverpool after Preston defeat?
Following Friday's behind-closed-doors loss, Liverpool are now set to jet off for their tour of the USA, where they will take on Real Betis (July 26), Arsenal (July 31) and Manchester United (August 3).
Slot's side then conclude their preparations for the new season against Sevilla at Anfield on August 11, six days before travelling to newly-promoted Ipswich Town in their Premier League opener.