Background: Many studies have investigated the efficacy of acupuncture in treating depression, but the mechanism of acupuncture for depression is still controversial and there is a lack of meta-analysis of mechanisms. Consequently, we investigated acupuncture's efficacy and mechanism of depression. Methods: We searched the Cochrane Library, PubMed, EMBASE, Web of Science. The SYRCLE Risk of Bias Tool was used to assess bias risk. Meta-analysis was performed using Stata 15.0 for indicators of depression mechanisms, body weight and behavioral tests. Results: A total of 22 studies with 497 animals with depressive-like behaviors were included. Meta-analysis showed that acupuncture significantly increased BDNF [SMD = 2.40, 95% CI (1.33, 3.46); I-2 = 86.6%], 5-HT [SMD = 2.28, 95% CI (1.08, 3.47); I-2 = 87.7%] compared to the control group (p < 0.05), and significantly reduced IL-1 beta [SMD = -2.33, 95% CI (-3.43, -1.23); I-2 = 69.6%], CORT [SMD = -2.81, 95% CI (-4.74, -0.87); I-2 = 86.8%] (p < 0.05). Acupuncture improved body weight [SMD = 1.35, 95% CI (0.58, 2.11); I-2 = 84.5%], forced swimming test [SMD = -1.89, 95% CI (-2.55, -1.24); I-2 = 76.3%], open field test (crossing number [SMD = 3.08, 95% CI (1.98, 4.17); I-2 = 86.7%], rearing number [SMD = 2.53, 95% CI (1.49, 3.57); I-2 = 87.0%]) (p < 0.05) compared to the control group. Conclusion: Acupuncture may treat animals of depressive-like behaviors by regulating neurotrophic factors, neurotransmitters, inflammatory cytokines, neuroendocrine system.