<p>Immunotherapy (IMMUNO) and targeted therapy (TT) have revolutionised melanoma treatment. However, adverse events (AEs) remain frequent and may affect treatment adherence. Female sex has been linked to a higher risk of AEs in cytotoxic therapies. This systematic review and meta-analysis investigate the effect of Sex and Gender (S/G) on AEs during IMMUNO and/or TT in melanoma. Independent studies published up to April 2024 reporting toxicity by S/G in melanoma patients were included. Summary Odds Ratios (sOR) and 95% Confidence Intervals (CI) were calculated using random-effects models. Sixty-nine studies were included. Women had a significantly higher risk of thyroid-related AEs compared to men (sOR = 2.00, 95% CI: 1.41–2.82, <i>I</i>² = 32%). No significant S/G differences were found for Grade III-IV, dermatological, gastrointestinal, hypophysis, kidney, liver, or ocular toxicities. This meta-analysis highlights a S/G based difference in the occurrence of thyroid-related AEs, particularly during first-line treatment. The observed association of dermatological AEs with TT in women, while intriguing, is based on limited evidence and should be considered hypothesis-generating. Overall, these findings suggest the need for closer monitoring of women for thyroid-related, dermatological, and severe AEs, with future studies warranted to confirm these signals in larger, adequately powered cohorts.</p><p></p>