<p>Fibroblast growth factor 21 (FGF21) is a liver-derived hormone known to suppress alcohol consumption in mice and non-human primates. However, the role of FGF21 in modulating environmental and behavioural factors driving alcohol consumption—such as cue-driven responses and effortful actions to obtain alcohol—and its effects on neural activity related to consumption, remain unclear. Here, we evaluated the impact of PF-05231023, a long-acting FGF21 analogue, across multiple dimensions of alcohol consumption and motivation and examined consumption-related activity in the nucleus accumbens. PF-05231023 reduced alcohol intake and preference in a dose- and sex-specific manner; diminished approach behaviours following an alcohol but not sucrose cue; and decreased lever-pressing under a progressive-ratio schedule, both alone and when combined with the Glucagon-like peptide-1 (GLP-1) agonist Exendin-4; it did not reduce lever-pressing for sucrose in alcohol-naïve mice. Additionally, PF-05231023 altered the microstructure of alcohol consumption by shortening drinking bouts and increased the recruitment of nucleus accumbens (Acb) neurons associated with bout termination as determined by micro-endoscopy of GCaMP7f. These findings demonstrate that PF-05231023 broadly suppresses alcohol-motivated behaviours without impacting natural reward and that targeting FGF21 signaling in combination with GLP-1 agonists may enhance therapeutic efficacy. Mechanistically, the observed reductions in alcohol consumption following PF-05231023 may involve diminished alcohol palatability and modulation of neuronal activity from distinct subsets of Acb neurons.</p>