Background: Tyrosine kinase inhibitors (TKIs) are effective therapies for various malignancies but are frequently associated with hepatotoxicity that may require dose modification or treatment interruption. This study aimed to investigate genetic susceptibility to TKI-induced hepatotoxicity. Methods: A cohort of TKI-treated patients was constructed using data from the All of Us Research Program. Hepatotoxicity was defined as grade ≥2 liver enzyme elevation according to CTCAE criteria. A genome-wide association study (GWAS) was performed using a suggestive threshold of P < 1 × 10⁻⁵. Multivariable logistic regression and polygenic risk score (PRS) analyses were conducted based on GWAS-identified variants. Results: Among 811 participants exposed to TKIs, 98 developed hepatotoxicity and 713 served as controls. Several loci exceeded the suggestive threshold, with the strongest association observed at rs72734306. Additional signals were detected near genes involved in immune regulation and endoplasmic reticulum stress pathways. In adjusted analyses, selected variants remained associated with hepatotoxicity, whereas clinical covariates were not independently significant. PRS analysis showed a trend toward increased risk with higher scores. Conclusions: Genetic variants, particularly those related to immune and ER stress pathways, may contribute to TKI-induced hepatotoxicity and support pharmacogenomic risk stratification.