BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of chemotherapy that affects the sensory, motor, and autonomic nerves. CIPN often leads to extremity dysfunction and reduced quality of life (QOL). Pharmacological therapies, such as duloxetine, have demonstrated efficacy in managing CIPN, and rehabilitation has emerged as a promising non-pharmacological treatment; however, the optimal exercise protocol remains unclear. Recent studies have suggested that home-based rehabilitation is feasible and safe for patients with cancer. This study aimed to evaluate the feasibility and safety of a 12-week hybrid intervention, combining outpatient supervision with home-based self-exercise in patients with CIPN. METHODS: This prospective observational study included 25 patients (17 women; mean age, 65.0 ± 9.3 years) with CIPN, 88% of whom had advanced or recurrent cancer. The intervention encompassed supervised outpatient rehabilitation sessions led by physical and occupational therapists and self-exercises at home. Primary outcomes included rehabilitation program completion and training adherence rates. Secondary outcomes included sensory nerve function, physical function, manual dexterity, QOL, and chemotherapy adherence. Descriptive statistics were used to summarize adherence rates. For the analysis of continuous variables, missing data were assumed to be missing at random and were handled using multiple imputation (MI), followed by generalized linear models (GLM). A total of 100 imputations were generated to ensure the stability and reliability of the estimates. RESULTS: The study completion rate was 76.0%, with an 88% adherence rate for both supervised and self-exercise components. The MI-based analysis showed significant improvements in physical function from T1 to T3, as measured by the Cancer Functional Assessment Set (β = 6.65, 95% CI: 0.2-13.0, p < 0.05), whereas sensory nerve function, manual dexterity, and QOL remained unchanged. Chemotherapy adherence remained favorable throughout the program. CONCLUSION: The present study demonstrated the feasibility and safety of a combined outpatient-supervised and home-based exercise intervention for patients with CIPN. These findings highlight the practicability of incorporating an exercise regimen into a CIPN management protocol to support ongoing chemotherapy. TRIAL REGISTRATION: This study was retrospectively registered in the University Hospital Medical Information Network Clinical Trials Registry on 19/11/2024 (UMIN-CTR ID: UMIN 000056201).