In this comprehensive overview of chemotherapy-induced liver injury, various classes of chemotherapeutic agents were reviewed to elucidate the complex cellular events contributing to hepatotoxicity and potential mitigation strategies. Alkylating agents, such as cyclophosphamide and busulfan, exhibited diverse mechanisms, with compounds like fucoidan and pyrroloquinoline quinone demonstrating protective effects through modulation of Nrf2/HO-1 and NF-κB pathways. Methotrexate-induced hepatotoxicity, characterized by oxidative stress and inflammation, highlighted the importance of addressing disruptions in lipid metabolism and the gut-liver axis. The multifaceted nature of cisplatin-induced liver damage emphasized the role of gastrointestinal microbiota and therapeutic interventions like curcumin. Anthracyclines, including doxorubicin and epirubicin, posed challenges in mitigating severe hepatotoxicity, with potential protective agents identified. Topoisomerase inhibitors, plant alkaloids, and antitumor antibodies showcased diverse impacts on liver function, emphasizing the need for tailored interventions. Targeted therapies, immune checkpoint inhibitors, and miscellaneous agents like L-asparaginase revealed distinct patterns of hepatotoxicity, prompting a nuanced understanding of patient safety. This comprehensive exploration offers a foundation for future research and therapeutic developments to enhance patient outcomes during chemotherapy.