Jutta Rantala scored twice in the landmark display at Prenton Park, as City got back to winning ways and confirmed their spot in the final four of this year's competition.
LCFC Women Assistant Manager Jennifer Foster and First Team Coach Stephen Kirby took charge of the team, as Willie Kirk continues to assist the Club with an internal process.
There were two changes to the side that were beaten by Chelsea the week prior, with Yuka Momiki and Josie Green replaced by Sophie Howard and Emilia Pelgander who made her first start for the Club.
The first 10 minutes in Tranmere saw Leicester hold most of the possession, and although the midfield of Sam Tierney and Saori Takarada were doing well to retain the ball, not many chances fell Leicester's way.
Fifteen minutes in, the visitors did break the deadlock through Rantala who netted her seventh goal of the season. Janice Cayman made a clever run in-behind the Liverpool defence and Tierney found, before the Belgium international fired an effort onto the post, but Rantala was there to convert the rebound.
Liverpool had their best couple of the chances over the following 15 minutes, first of all when a shot from range forced Lize Kop to dive to her bottom left and make the stop, before the 'keeper caused a moment of panic in the Leicester camp.
Trying to play out from the back, the Dutch shot-stopper played the ball straight to Marie Höbinger, but with Kop scrambling, the Liverpool forward could only clip the ball onto the post.
Little over the hour mark, City gained themselves some breathing space when Aileen Whelan, who had performed well in the striker position, played Rantala out wide. The No.8 cut inside and fired the ball over the Reds' 'keeper, striking the underside of the crossbar on its way in.
Lena Petermann and Momiki were introduced late on into the game and helped the Foxes to dictate play, while Asmita Ale also had an impressive second-half cameo appearance at full-back.
With the clock ticking down, Liverpool never really looked to threaten the Foxes' backline, as the cheers from the away end marked the conclusion of the match, sending Leicester into the semi-final for the first time in their history.