Introduction It has been suggested that fluoroquinolone antibiotics increase the risk of developing collagen-associated adverse events such as aortic dissection and aortic aneurysm. These are life-threatening emergencies that need to be prevented. Objectives We performed this systematic review to clarify the association between fluoroquinolones and three collagen-associated adverse events: aortic aneurysm or aortic dissection, retinal detachment, and tendon disorders. Methods We searched PubMed, Embase, and Scopus for observational studies up to January 2019. Cohort and case-control studies were included if they reported data on the risk of collagen-related adverse events associated with fluoroquinolone exposure versus no exposure. We assessed the quality of the included studies using the Newcastle-Ottawa Scale. Effect statistics were pooled using random-effects models. Sensitivity and subgroup analyses were performed to identify any source of heterogeneity. Results After screening 2729 citations, we included 22 observational studies (12 cohort studies and ten case-control studies) with 19,207,552 participants. Current use of fluoroquinolones was significantly associated with aortic aneurysm and aortic dissection (odds ratio [OR] 2.20; 95% confidence interval [CI] 1.92-2.52), tendon disorders (OR 1.89; 95% CI 1.53-2.33), and retinal detachment (sensitivity analysis, OR 1.25; 95% CI 1.01-1.53). Past fluoroquinolone use (> 30 and <= 365 days) was associated with retinal detachment (OR 1.27; 95% CI 1.09-1.47). Conclusions Fluoroquinolone use incurs a risk of developing three collagen-associated diseases (aortic aneurysm or aortic dissection, retinal detachment, and tendon disorders). Patients at an increased risk of collagen-associated diseases should not use fluoroquinolones unless no other options are available.