Zearalenone (ZEA) is a common estrogenic mycotoxin in rabbit breeding that causes various toxic effects. Selenomethionine (SeMet) is a feed additive with potent anti-inflammatory and antioxidant properties. To evaluate the protective role and action mechanism of SeMet against ZEA-induced liver injury, 90-day-old rabbits were randomized into five groups: control, ZEA-alone, and SeMet pretreatment at 0.2, 0.35, and 0.5 mg/kg. SeMet was administered for 21 days, followed by continuous intragastric ZEA (1.2 mg/kg B.W.) for 7 days starting on day 15. As a result, ZEA exposure significantly elevated liver function parameters, disrupted lobular architecture, and impaired glycogen synthesis. It also induced liver oxidative stress, thus upregulating expressions of Bax, Cyt C, Caspase-3, and Caspase-9, triggering hepatocyte apoptosis, mitochondrial damage, and mitophagy. SeMet pretreatment activated SIRT1, reduced the acetylated FOXO1/P53 levels, and enhanced CAT and SOD2 expression, mitigating ZEA-induced oxidative stress, apoptosis, and mitophagy. Based on the above findings, SeMet’s alleviating effect might be mediated via the SIRT1-FOXO1/P53 pathway, with 0.35 mg/kg of SeMet exerting the optimal efficacy, highlighting its therapeutic potential for mitigating ZEA-induced hepatotoxicity in rabbits.