Background: Depression is associated with an increase in the likelihood of cardiac events; however, studies investigating the relationship between depression and heart rate variability (HRV) have generally focused on patients with cardiovascular disease (CVD). The objective of the current report is to examine with meta-analysis the impact of depression and antidepressant treatment on HRV in depressed patients without CVD. Methods: Studies comparing 1) HRV in patients with major depressive disorder and healthy control subjects and 2) the HRV of patients with major depressive disorder before and after treatment were considered for meta-analysis. Results: Meta-analyses were based on 18 articles that met inclusion criteria, comprising a total of 673 depressed participants and 407 healthy comparison participants. Participants with depression had lower HRV (time frequency: Hedges’ g = −.301, p textless .001; high frequency: Hedges’ g = −.293, p textless .001; nonlinear: Hedges’ g = −1.955, p = .05; Valsalva ratio: Hedges’ g = −.712, p textless .001) than healthy control subjects, and depression severity was negatively correlated with HRV (r = −.354, p textless .001). Tricyclic medication decreased HRV, although serotonin reuptake inhibitors, mirtazapine, and nefazodone had no significant impact on HRV despite patient response to treatment. Conclusions: Depression without CVD is associated with reduced HRV, which decreases with increasing depression severity, most apparent with nonlinear measures of HRV. Critically, a variety of antidepressant treatments do not resolve these decreases despite resolution of symptoms, highlighting that antidepressant medications might not have HRV-mediated cardioprotective effects and the need to identify individuals at risk among patients in remission.