Serotonin stimulation of the 5HT4 receptor might be responsible for an increased risk of atrial fibrillation (AF). Thus, we assessed whether the use of antidepressants (ADs) is associated with an increased risk of chronic AF (cAF). Using the UK Clinical Practice Research Datalink, a nested case-control analysis was conducted within a cohort of new AD users having a diagnosis of depression and/or anxiety. Cases of cAF occurring during follow-up were individually matched with up to 10 controls on age, sex, year of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) of cAF associated with current and recent use of ADs, when compared to past use. The cohort included 116,125 new AD users, of whom 1,271 were diagnosed with cAF during follow-up (incidence rate: 1.6 per 1,000 person-years). The adjusted RR of cAF associated with current and recent use of ADs was 0.98 (95%CI: 0.86–1.12) and 1.02 (95%CI: 0.86–1.30), respectively. No association was observed when ADs were classified according to their potency in reducing serotonin reuptake. These findings suggest that exposure to ADs is not associated with an increased risk of cAF.