Background: Evidence-based treatments for adult depression include psychotherapy and pharmacotherapy, yet little is known about how baseline depression severity moderates treatment outcome. Objectives: We aimed to compare the effects of psychotherapy and pharmacotherapy for adult depression and to examine the association between baseline depression severity and treatment outcome, converting multiple baseline depression measures into the scores of the Beck Depression Inventory, second edition (BDI-II). Methods: We conducted systematic searches in bibliographical databases up to September 2022 to identify randomized controlled trials (RCTs) in which psychotherapy was compared with pharmacotherapy in the treatment of adult depression. Various meta-regressions using the baseline depression severity as predictor of the relative effects of psychotherapy and pharmacotherapy were performed. Results: We identified 65 RCTs including 7250 participants for the meta-analyses and 56 RCTs including 5548 participants for the meta-regression. We found no significant difference between psychotherapy and pharmacotherapy (g = −0.08, 95 % CI: −0.2 to 0.04, p = 0.193) and baseline depression severity was not significantly associated with the relative effects of psychotherapy and pharmacotherapy (B = 0.0032, SE = 0.0096, p = 0.74). Results were similar in several sensitivity analyses. Limitations: Limitations included the low quality of the included studies, and the omission of long-term effects and within-study variability. Conclusions: We found no indication for a moderation effect of baseline depression severity on the relative effects of psychotherapy and pharmacotherapy. Thus, other factors such as availability and patients' preference must be considered when deciding for treatment options.