<p>Skin cancer represents approximately 7.5% of all cancer cases globally, with conventional therapies often associated with substantial adverse effects. Silibinin, a natural flavonolignan derived from milk thistle seeds, has demonstrated promising anti-cancer properties in preclinical studies. This meta-analysis assesses the therapeutic and preventive potential of silibinin in animal models of skin cancer. A systematic literature search was conducted across PubMed, Embase, Web of Science, and Scopus databases (1990–2024) following PRISMA 2020 guidelines. Studies were selected based on PICOS criteria, with tumor volume as the primary outcome and tumor count, incidence rate, proliferating cell nuclear antigen (PCNA) expression, and body weight as secondary outcomes. Risk of bias was assessed using the SYRCLE tool. Data were synthesized using a random-effects model, and standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Seven studies comprising 193 silibinin-treated and 83 control animals were included. Silibinin significantly reduced tumor volume (SMD =  − 1.23; 95% CI − 1.44 to − 1.01) with no heterogeneity (<i>I</i>² = 0%). Significant reductions were also observed in tumor count (SMD =  − 2.41; 95% CI − 3.19 to − 1.64) and PCNA expression (SMD =  − 3.61; 95% CI − 4.82 to − 2.40), while tumor incidence showed a non-significant decrease. Subgroup analyses indicated no significant differences in tumor volume reduction based on the route or timing of silibinin administration. However, topical application and pre-treatment were more effective in lowering PCNA levels. These findings suggest that silibinin holds significant potential as a preventive and therapeutic agent against skin cancer in preclinical settings.</p>