Cadmium (Cd²⁺) contamination severely threatens aquatic organisms, leading to oxidative stress, inflammation, and hepatotoxicity. Portulaca oleracea is known for its antioxidant and anti-inflammatory activities; yet, its defensive role against Cd²⁺-induced hepatotoxicity in Nile tilapia (Oreochromis niloticus) is still unclear. The current study evaluated the possible hepatoprotective effects of purslane leaf powder (PR) against Cd²⁺-induced liver damage and its mechanisms. A hepatotoxicity model was established by exposing tilapia to Cd²⁺ (50 µg/L) for 60 days, with and without PR supplementation (10 g PR/kg diet). Histopathological analysis, biochemical assays, and real-time quantitative PCR were done to assess liver tissue damage, oxidative stress markers, lipid profile, and inflammatory gene expression. Results showed that Cd²⁺ exposure induced severe hepatic alterations, including glycogen depletion, steatosis, necrosis, and inflammatory infiltration, along with increased liver indices and obvious dyslipidemia. PR supplementation significantly alleviated these changes by reducing oxidative stress, enhancing antioxidant enzyme activity, upregulating antioxidant genes (sod-1, sod-2, cat, gpx, and cyp1a), and downregulating inflammatory markers (mapk1, nf-κb, il1β, il6, il8, and tnf-α). Additionally, PR improved lipid profile and liver morphology, and reduced hepatocyte damage compared to the Cd²+-exposed group. In conclusion, PRP mitigates Cd²⁺-induced hepatotoxicity in Nile tilapia by enhancing antioxidant defenses and reducing inflammation, suggesting its potential as a dietary supplement to counteract heavy metal toxicity in aquaculture.