Steven Gerrard's early penalty was enough to give Liverpool the advantage after playing out a 1-0 victory over Manchester City, condemning the hosts to a second consecutive defeat at the Etihad Stadium.
After being knocked out of the FA Cup by local rivals Manchester United on Sunday, the Citizens suffered back-to-back home losses for the first time since February 2008.
The Reds started brightly and forced a succession of outstanding saves from City goalkeeper Joe Hart who kept the scoreline level, until Stefan Savic fouled Daniel Agger in the box with a reckless challenge on 13 minutes.
Gerrard converted from the spot to break the deadlock, and was central to Liverpool's dominance in the first-half, particularly in midfield.
However, Kenny Dalglish's side suffered a setback when Jay Spearing pulled up suddenly with an injury and had to be replaced by Charlie Adam.
Mario Balotelli was withdrawn before half-time, in place of Samir Nasri, who quickly called Pepe Reina into action with his first real save of the game.
City gained momentum in the second half and started to exert their pressure, but without influential duo Yaya Toure and David Silva, it was abundantly clear that a creative spark was missing from Roberto Mancini's side.
Edin Dzeko replaced Adam Johnson with a little under half an hour remaining, but the changes did little to break down a resolute Liverpool defence, who held on to take the advantage back to Anfield when the two sides meet in the second leg in a fortnight's time.