The most effective means of preventing seasonal influenza is through vaccination. In this systematic review, we investigated the efficacy, effectiveness and safety of MF59^® adjuvanted trivalent and quadrivalent influenza vaccines to prevent laboratory‐confirmed influenza. A systematic literature search was conducted in electronic databases and grey literature sources up to 7 February 2020. Randomised controlled trials and non‐randomised studies of interventions (NRSIs) were eligible for inclusion. The search returned 28,846 records, of which 48 studies on MF59^® adjuvanted vaccines met our inclusion criteria. No efficacy trials were identified. In terms of vaccine effectiveness (VE), MF59^® adjuvanted trivalent influenza vaccines were effective in preventing laboratory‐confirmed influenza in older adults (aged ≥65 years) compared with no vaccination (VE = 45%, 95% confidence interval (CI) 23%–61%, 5 NRSIs across 3 influenza seasons). By subtype, significant effect was found for influenza A(H1N1) (VE = 61%, 95% CI 44%–73%) and B (VE = 29%, 95% CI 5%–46%), but not for A(H3N2). In terms of relative VE, there was no significant difference comparing MF59^® adjuvanted trivalent vaccines with either non‐adjuvanted trivalent or quadrivalent vaccines. Compared with traditional trivalent influenza vaccines, MF59^® adjuvanted trivalent influenza vaccines were associated with a greater number of local adverse events (RR = 1.90, 95% CI 1.50–2.39) and systemic reactions (RR = 1.18, 95% CI 1.02–1.38). In conclusion, MF59^® adjuvanted trivalent influenza vaccines were found to be more effective than ‘no vaccination’. Based on limited data, there was no significant difference comparing the effectiveness of MF59^® adjuvanted vaccines with their non‐adjuvanted counterparts.