BH-3 like motif containing inducer of cell death (BLID) is a known prognostic factor in breast cancer. The aim of the present study was to determine the significance of BLID in the outcomes of chemotherapy and mechanisms affected in BLID-deficient breast cancer cells. Reverse transcription-PCR, reverse transcription-quantitative PCR, dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine the effects of drugs on BLID expression and binding of forkhead box protein O3a (FOXO3a) to the BLID promoter. RNA arrays, antibody microarrays and microRNA arrays were used to illuminate the omics features of BLID knockdown vs. isogenic control breast cancer cell lines. Kaplan-Meier plotter and receiver operating characteristic plotter tools were used to determine the prognostic and therapy response benefits of BLID expression using publicly available clinical datasets. BLID expression was induced in response to several chemotherapeutic drugs. Drug treatment resulted in increased binding of FOXO3a to the BLID promoter, and FOXO3a knockdown was associated with decreased expression of BLID. BLID depletion led to a decrease in the cytotoxicity of chemotherapeutic drugs. Through multi-omics profiling, three functionally distinct classes of effectors that were predominately influenced in BLID knockdown cells were identified: i) Genes and proteins associated with cell death and survival, including cellular inhibitor of apoptosis protein 2/baculoviral IAP repeat containing 3, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α/p110α and DFNA5/gasdermin E; ii) members of the aldo-ketoreductase family 1, specifically aldo-keto reductase family 1 member C3 implicated in drug metabolism; and iii) effectors of the interferon response, including IFNβ1, interferon-induced protein with tetratricopeptide repeats 2 and interferon-induced protein with tetratricopeptide repeats 3. Finally, higher BLID expression was associated with improved overall survival in several types of cancer and the response of breast cancer to anthracyclines. The results of the present study demonstrated that BLID is a target of FOXO3a, and BLID-deficiency in breast cancer cells was associated with modulation of cell death, survival and proliferation, chemoresistance, drug potency, and the interferon response. These findings highlighted BLID as a promising biomarker of drug response and offer a novel framework of integrative mechanisms of therapeutic resistance and disease progression.