Hepatocellular carcinoma (HCC) is a global challenge with a high cancer-related death rate. Although BCL2L12 has been reported to be upregulated in mice with HCC, and its deletion markedly inhibits HCC progression, its specific role and associated tumorigenesis mechanisms in human HCC remain elusive. Differential gene expression analysis was performed using TCGA and GEPIA databases. Survival probability analysis was conducted using the Kaplan-Meier method. Immune checkpoint-related prognosis in HCC and their correlation with BCL2L12 were analyzed. The correlation between BCL2L12 and immune infiltration was investigated using the TIMER database. MEXPRESS and MethSurv were employed to display methylation of BCL2L12 and prognostic value. Upstream ncRNAs of BCL2L12 were predicted using starBase, String and TargetScan. Protein-protein interaction network involving BCL2L12 was constructed via String. Genes related to BCL2L12 in HCC were obtained from the LinkedOmics database. BCL2L12-targeted drugs for HCC were predicted via RNAactDrug, Enrichr, CTD, and NetworkAnalyst. BCL2L12 expression was upregulated and associated with poor prognosis in HCC. BCL2L12 showed significant co-occurrence with an immune checkpoint, namely TNFRSF4. BCL2L12 was significantly associated with immune infiltration in HCC. Cg03848533 methylation and CYTOR/MIR4435-2HG-has-miR-125b-5p axis regulated BCL2L12 expression and prognosis of HCC. BCL2L12 interacted with ZNF215 and PUSL1, all of which were independent risk factors for overall survival in patients with HCC. Panobinostat, Pirinixic acid, and Fluorouracil were predicted to be the potential BCL2L12-targeted drug for HCC. Our findings offer an understanding of the Oncogenic Role of BCL2L12 associated with immune status in the prognosis of HCC and provide potential strategies for currently limited treatment.© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.