Background: Depression will become the second most common disease after coronary heart disease (CHD). Escitalopram and olanzapine are commonly used to treat depression. Some studies indicated that escitalopram combined with olanzapine is effective in treating depression, however, there is no evidence to support these results. Our objective was to study the efficacy of escitalopram combined with olanzapine on depression by conducting a systematic review and meta analysis, and to provide reference for doctors. Methods: Relevant evidence were searched from PubMed, SinoMed, the Cochrane Library, Web of Science, Embase, China Knowledge Resource Integrated (CNKI), Wanfang Data Knowledge Service Platform databases (WANFANG) and VIP dating from inception to July 2020. The randomized controlled trials (RCTs) of escitalopram and olanzapine for the treatment of depression was obtained. According to inclusion and exclusion criteria, two researches (Sun Wu and Wang Zhe) independently screened the literature, extracted data, and evaluated the quality of included studies. Rev Man 5.3 software was used to conduct statistical analyze. Results: A total of 39 studies involving 3,267 patients were identified. These studies were finally included into the meta-analysis. Pooled results showed that there was a significant difference in efficiency (RR=1.18, 95％CI: 1.14 to 1.12, P<0.00001), HAMD (MD=-4.54, 95％CI: -5.09 to -3.99, P<0.00001), and HAMA (MD=-3.94, 95％CI: -5.57 to -2.12, P<0.0001). There was no significant difference in adverse reactions (MD=0.07, 95％CI -0.03 to 0.17, P=0.19). Heterogeneity test showed that due to the high heterogeneity of HAMD (P<0.00001, I2=86％) and HAMA (P<0.00001, I2=91％), after removing the items with high heterogeneity, there were also statistically significant in HAMD (MD=-5.22, 95％CI: -5.53 to -4.91, P<0.00001) and HAMA (MD=-5.46, 95％CI: -6.15 to -4.77, P<0.00001). Conclusion: Based on this study, the combination of escitalopram and olanzapine was more effective in treating depression than the control group. It is suggested that clinical and scientific researchers carry out more high-quality, large-sample, multi-center RCTs to provide more evidence-based medical evidence for the future study of escitalopram combined with olanzapine in the treatment of depression.