Background Our goal was to quantify the risk of hyperhidrosis associated with commonly used antidepressant agents and examine the impact of medication class, pharmacodynamics, and dose on risk of hyperhidrosis. Methods We conducted a PubMed search to identify all double‐blind, randomized, placebo‐controlled trials examining the efficacy of second‐generation antidepressant medications in the treatment of adults with a depressive disorder, anxiety disorders, or obsessive‐compulsive disorder. We used a random‐effects meta‐analysis to examine the pooled risk ratio of hyperhidrosis reported as a side effect in adults treated with second‐generation antidepressants compared to placebo. We used stratified subgroup analysis and metaregression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of hyperhidrosis. Results We identified 76 trials involving 28,544 subjects. There was no significant difference in the risk of hyperhidrosis between serotonin–norepinephrine reuptake inhibitors (SNRI) [risk ratio (RR) = 3.17, 95% CI: 2.63–3.82] and selective serotonin reuptake inhibitors (SSRI) (RR = 2.93, 95% CI: 2.46–3.47) medications compared to placebo. All antidepressant medications were associated with a significantly increased risk of hyperhidrosis except fluvoxamine (RR = 0.56, 95% CI: 0.12–2.53), bupropion (RR = 1.23, 95% CI: 0.57–2.67), and vortioxetine (RR = 1.35, 95% CI: 0.79–2.33). The dose of SSRI/SNRI medications was not significantly associated with the risk of hyperhidrosis. Increased risk of hyperhidrosis was associated with increased affinity of SSRI/SNRI medications to the dopamine transporter. Conclusion Risk of hyperhidrosis was significantly increased with most antidepressant medications but was associated with dopamine transporter affinity.