PURPOSE: The objective is to evaluate the effectiveness and safety of calcium ionophore as an artificial oocyte activation (AOA) method on pregnancy outcomes in different groups of intracytoplasmic sperm injection (ICSI) patients, providing potential evidence to establish consensus on the indications of AOA. METHODS: A systematic comprehensive search was performed in Medline, Embase, the Cochrane Library, and Google Scholar databases. Studies published from January 2014 to June 2024 were searched for analysis. All studies that compared ICSI with AOA-ICSI in routine indications composing impaired fertilization or embryo developmental arrest in previous cycles, or male-factor infertility were included. RESULTS: Twelve studies were included in the meta-analysis. AOA-ICSI was associated with the increase in the overall fertilization rate (OR 1.99, 95% CI 1.16-3.41) and live birth rate (OR 4.58, 95% CI 1.52-13.80). All secondary outcomes including cleavage, blastocyst, high-quality embryo, implantation, biochemical pregnancy, clinical pregnancy presented superiority or equivalence in AOA-ICSI. And the use of calcium ionophore did not increase the miscarriage rate (OR 0.43, 95% CI 0.08-2.43). In subgroup analysis, AOA-ICSI exhibited a more significant effect on patients with indications of no or low fertilization. However, in patients with non-fertilization factors, no statistically significant improvements were observed in all outcomes. CONCLUSION: Calcium ionophore is an effective artificial oocyte activation approach to improving pregnancy outcomes after ICSI, particularly in cases with indications of fertilization factors, providing further support for the application of AOA in specific populations. Further validation is needed to comprehensively establish the safety of AOA. TRIAL REGISTRATION: PROSPERO registration number CRD42024551481.