Background: Concerns of COVID-19 vaccine safety from pregnant women still widespread. We used transcriptomic profile analysis to study changes of the maternal-fetal interface after vaccination and explore the possible protective effects from vaccination against miscarriage. Methods: We collected decidual tissuesafter uterine curettage from pregnant women in the first trimister with (n = 6) and without a COVID-19 vaccination (n = 6) and performed RNA-sequencing. Furthermore, we ananlyzed our transcriptome datas of samples and other datasets about maternal-fetal interface and miscarrige to analyze the potential link by bioinformatics tools. Results: We identified 879 different expressed genes from pregnant women who received vaccination and found that the COVID-19 vaccine could alter some hazardous RSA-related genes, such as CXCL11, FOS, FOSB, LY96, MMP10, and NCF2. Vaccination also changed some hazardous RSA-related signaling pathway.These molecules induced the transformation of M2 macrophages and promoted the balance of Th1/Th2 immune responses. Finally, these effects on the immune microenvironment of the maternal-fetal interface also showed corresponding positive changes. Conclusion: Many RSA-related signaling molecules were reversed after COVID-19 vaccination, indicating that the vaccine did not cause RSA, and these molecules ultimately may have protective effects on miscarriage by influencing the immune microenvironment at the maternal-fetal interface.