The real-world evidence data from multiple sources which includes information on patient health status and medical behavior in routine clinical setup can give deeper insights into drugs ‘safety and efficacy. The RWE-based analysis in this study revealed a statistically significant link between biologics usage and hepatotoxicity in patients. To the best of our knowledge, this study is the first to conduct a large-scale multi-cohort analysis on the hepatotoxic profiles of biologics. Biologics are among the most prescribed medicines for several chronic inflammatory diseases. These agents target critical pathogenic pathways, but they may also have serious side effects. It is important to analyze whether biologics agents are an added concern or therapeutic opportunity. Real-world evidence (RWE) data were extracted for patients using biologics to monitor the safety and effectiveness of the biologics. All six biologics included in this analysis—are mostly highly prescribed biologics. The aim of the study was to assess the hepatotoxic profiles of subjects using different biologics. We evaluated the safety of current treatment regimens for patients in a large real-world cohort from multiple health care centers. Total number of eligible patients retrieved from the database is 38,112,285. Of these 38 million patients, 2.3 million take biologics. The primary objective was to assess the potential adverse hepatotoxic effects of the six biologics; adalimumab, trastuzumab, prevnar13, pegfilgrastim, interferon-beta1a and insulin glargine across different indications like diabetes mellitus, encounter for immunization, malignant neoplasm of breast, multiple sclerosis, malignant neoplasm of kidney, aplastic anaemias, radiation sickness, Crohn's disease, psoriasis, rheumatoid arthritis, spondylopathies. Data from patients using the six most-used biologics-adalimumab, trastuzumab, prevnar13, pegfilgrastim, interferon-beta1a and insulin glargine were retrieved from a global research network covering 250 million patients’ data from 19 countries, and assigned to the cohorts 1 and 2, respectively. The cohorts were propensity score matched for age and sex. After defining the primary outcome as “hepatotoxicity” (endpoint defined as ICD-10 code: K71 (hepatotoxic liver disease), a Kaplan–Meier survival analysis was performed, and risk ratios (RR), odds ratios (OR), and hazard ratios (HR) were determined. A total number of 2,312,655 subjects were eligible who take biologics, and after matching total cohorts accounted for 2,303,445. We have considered the clinical data as a 1:1 matched‐study design, using propensity score‐matched sub‐cohorts to better control for confounding associations that might stem from different distributions of age and gender between the whole dataset and the subset of patients. We discovered evidence supporting the hepatotoxic-causing effect of biologic drugs: (i) all biologics considered together had an OR of 1.9 (95% CI, 1.67–2.35), with (ii) Adalimumab 1.9 (95% CI, 1.72–2.20), Trastuzumab 1.7 (95% CI, 1.2–2.3), Prevnar13 2.3 (95% CI, 2.16–2.60), Pegfilgrastim 2.3 (95% CI, 2.0–2.50), Interferon-Beta1a 1.7 (95% CI, 1.18–2.51), and Insulin glargine 1.9 (95% CI, 1.8–1.99). Our findings indicate that clinicians should consider evaluating hepatic profiles of patients undergoing treatment with biologic drugs and counsel them regarding the risk of developing hepatic injury. Strengths of the study includes a large sample size and robust statistical techniques. Limitations of this study include lack of detailed information regarding clinical severity. Major biologics are associated with hepatotoxicity. We discovered evidence supporting the hepatotoxicity-causing effects of biologics: all biologics considered together had an OR of 1.9 (95% CI, 1.67–2.35).