Injuries caused by cerebral ischemia reperfusion (CIR) can worsen neurological outcomes, Biliverdin (BV) is an antioxidant and anti-apoptotic agent that was shown to affect CIR, although the underlying mechanisms remain unclear. In this study, we investigated the role of BV and its potential underlying mechanism in CIR injury. CIR rat models and primary cortical neurons were established and treated with and without BV. Additionally, adenovirus vectors that could overexpress LncRNA H19 and overexpress or knock-down miR-181b-5p and Esm1 were created to investigate their regulation of molecular expression. Our findings showed that BV could significantly improve CIR injury, both in vivo and in vitro, decrease LncRNA H19 and Esm1 expression, and increase miR-181b-5p expression. Overexpression of LncRNA H19 inhibited the anti-injury effects of BV. Further, the down-regulation of miR-181b-5p or up-regulation of Esm1 expression weakened the in vitro protective effect of BV. RNA immunoprecipitation assay and dual luciferase reporter gene assay further confirmed that LncRNA H19 could sponge miR-181b-5p, and Esm1 was the target of miR-181b-5p. Rescue experiments confirmed that BV could regulate the LncRNA H19/miR-181b-5p/Esm1 molecular axis. Lastly, proteomic and bioinformatic analyzes revealed that Esm1 upregulation in BV-treated neurons resulted in the differential expression of 16 proteins, including 9 upregulated and 7 downregulated proteins. In conclusion, this study found that BV could ameliorate CIR injury by regulating the LncRNA H19/miR-181b-5p/Esm1 axis.