Camptothecin derivatives, such as CPT-11 (irinotecan), possess potent antitumor properties but are often hampered by their hydrophobic nature, leading to severe diarrhea as a common adverse effect. To address this challenge, we designed and synthesized novel highly hydrophilic camptothecin derivatives by conjugating SN38 with branched glycerol trimer (SN38-BGL). This unique strategy aimed to enhance the therapeutic benefits while minimizing the adverse effects. In murine xenograft models of human lung cancer, SN38-BGLs exhibited comparable or slightly superior tumor-suppressing efficacy compared to CPT-11 without the onset of early or late diarrhea. Additionally, histological analysis revealed that SN38-BGL treatment resulted in longer villi in the jejunum and ileum compared to CPT-11, indicating that SN38-BGL is less harmful. Digestion by liver microsome ex vivo did not yield SN38 but a few other molecules, suggesting possible involvement of other active metabolites than SN38. Our findings suggest that SN38-BGLs represent a promising class of hydrophilic camptothecin derivatives with the potential to mitigate severe diarrhea while maintaining antitumor efficacy, offering new prospects for pharmacological interventions.