•Fluoroquinolones (FQs) are reserve antimicrobials when no alternative treatment is available.•FQs are often prescribed as first-line treatment for less severe infections in primary care.•Central nervous system (CNS)- and gastrointestinal (GI)-related AEs with FQs three times that of any other antimicrobial.•Total AEs similar for FQs and other antimicrobials; more total AEs and GI-related AEs for co-amoxiclav compared with FQs.•No difference identified for skin-related or overall risk of AEs compared to any other antimicrobial. Fluoroquinolones (FQs) are second-line antimicrobial agents. Once the decision to prescribe an antimicrobial is made, the choice of antimicrobial should be based on both the benefits and adverse effects. This systematic review quantifies the occurrence of common adverse events (AEs) related to FQs in relation to any other antimicrobial for any indication in primary care. We searched randomized controlled trials from Embase, PubMed, Cochrane Central Register of Controlled Trials and CINHAL. FQs had to be administered orally, for any indication, to adults and in primary care. Data were extracted independently in standard forms in “Covidence”. Pooled estimates of the intervention effects for AEs were determined by the Peto odds ratios (ORs) and 95% confidence intervals (CIs) in Revman. In the 39 studies selected, the most commonly reported AEs were nausea, vomiting, diarrhoea, headache, dizziness, and rash. A meta-analysis of 28 studies reporting AEs showed central nervous system (CNS)-related AEs (OR 1.40 (1.12-1.75) P = 0.003, heterogeneity (I2) = 0%) and gastrointestinal (GI)-related AEs (OR 1.20 (1.06-1.36) P = 0.005, I2 = 80%) were significantly associated with FQs compared with other antimicrobials. Compared with FQs, co-amoxiclav showed significantly more total AEs (OR 0.70 (0.54-0.90) P = 0.006, I2 = 78%) and GI-related AEs (OR 0.69 (0.52-0.91) P = 0.008, I2 = 94%). Withdrawal or discontinuation due to drug-related AEs was higher for FQs (OR 1.19 (1.00-1.42) P = 0.05, I2 = 5%). Sensitivity analyses did not change these results. FQs are associated with more CNS- and GI-related AEs compared with other types of antimicrobial. This information is relevant to support decision making in relation to antimicrobial prescribing.