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Background: Melanoma, the most threatening cancer in the skin, has been considered to be driven by the carcinogenic RAF-MEK1/2-ERK1/2 signaling pathway. This signaling pathway is usually mainly dysregulated by mutations in BRAF or RAS in skin melanomas. Although inhibitors targeting mutant BRAF, such as vemurafenib, have improved the clinical outcome of melanoma patients with BRAF mutations, the efficiency of vemurafenib is limited in many patients. Methods: Spearman correlation analysis was performed to determine the relationship between blood bilirubin and clinical outcomes in a retrospective study. In vitro and in vivo assays were used to determine the effect of bilirubin on the sensitivity of melanoma cells to vemurafenib. Findings: Blood bilirubin in patients with BRAF-mutant melanoma treated with vemurafenib is negatively correlated with clinical outcomes. In vitro and animal experiments show that bilirubin can abrogate vemurafenib-induced growth suppression of BRAF-mutant melanoma cells. Moreover, bilirubin can remarkably rescue vemurafenib-induced apoptosis. Mechanically, the activation of ERK-MNK1 axis is required for bilirubin-induced reversal effects post vemurafenib treatment. Interpretation: Our findings not only demonstrate that bilirubin is an unfavorable for patients with BRAF-mutant melanoma who received vemurafenib treatment, but also uncover the underlying mechanism by which bilirubin restrains the anticancer effect of vemurafenib on BRAF-mutant melanoma cells. Funding: National Natural Science Foundation of China (81773213 and 81972399), Natural Science Foundation research team of Guangdong Province (2018B030312001), and the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital (202011-204, 202011-106). Declaration of Interest: None to declare Ethical Approval: This study was approved by Institutional Animal Care and Use Committee.