Background <p>Mental health issues, including depression, anxiety, and stress, are major contributors to the global disease burden and disability. Numerous preliminary studies have explored the effects of these conditions but reported inconsistent findings. Due to the lack of sufficient evidence in this area, the present study aimed to evaluate the impact of cognitive behavioral therapy (CBT) on depression, anxiety, and stress through a systematic review and meta-analysis.</p> Methods <p>This systematic review and meta-analysis included studies published up to December 2024. We retrieved relevant articles from the databases Embase, PubMed, Scopus, and Web of Science (WoS) using specific keywords. We assessed heterogeneity among studies using the <i>I</i>² index and performed statistical analysis with Comprehensive Meta-Analysis software.</p> Results <p>Initially, we identified a total of 84,264 studies, and after screening, 153 articles were included in the meta-analysis. The pooled results indicated that cognitive behavioral therapy significantly reduced scores for depression, anxiety, and stress in the intervention group compared to the control group, with mean reductions of 1.017 ± 0.103, 1.013 ± 0.073, and 1.209 ± 0.114, respectively (95% CI, <i>P</i> &lt; 0.001). The effectiveness of cognitive behavioral therapy was lower in studies with larger sample sizes and among older participants (<i>P</i> &lt; 0.05). The effect of CBT on depression in the general population and on anxiety and stress in cancer patients was higher than in other populations (<i>P</i> &lt; 0.05). The type of study (RCT or non-RCT) did not have a significant impact on the effect of CBT on depression, anxiety, and stress (<i>P</i> &gt; 0.05).</p> Conclusion <p>Cognitive behavioral therapy significantly reduces symptoms of depression, anxiety, and stress. Therefore, CBT shows promising outcomes for managing these conditions and should be considered by health professionals and policymakers.</p>