Abstract Background Despite excellent survival and elimination of cranial radiation, patients treated for acute lymphoblastic leukemia (ALL) in childhood remain at increased risk for chronic conditions, including peripheral neuropathy and sarcopenia. This study aimed to evaluate the association between peripheral neuropathy and sarcopenia in survivors of childhood ALL without prior cranial radiation exposure. Additionally, we explore the effects of neuropathy and sarcopenia on physical function and exercise behavior. Methods We included survivors of childhood ALL diagnosed between 1962 and 2012, aged ≥18 years without a history of cranial radiation from the St. Jude Lifetime Cohort Study (SJLIFE). Peripheral neuropathy was assessed using the Modified Total Neuropathy Score (mTNS). Sarcopenia was defined by low muscle mass (dual X-ray absorptiometry) and muscle weakness, with muscle strength assessed using hand grip and quadriceps strength tests. Physical function was evaluated with the Timed-Up-and-Go test and a 50-foot walk test. Physical activity was self-reported via the NHANES Physical Activity Questionnaire. Statistical analyses, including modified Poisson regression, were performed to examine associations. Results Among 537 survivors (median age: 28 years, range 18–52), 31.7% had peripheral neuropathy, 19.0% had reduced muscle strength, and 21.6% had reduced relative lean muscle mass. Neuropathy was significantly associated with impaired gait speed (RR: 1.31, 95% CI 1.01 to 1.7). Sarcopenia, particularly impaired muscle strength, was associated with impaired mobility (RR: 2.99, 95% CI 1.91 to 4.68), gait speed (RR: 1.45, 95% CI 1.06 to 1.97), and <150 min/week of moderate or vigorous physical activity (RR 1.43, 95% CI 1.04 to 1.95). Conclusion Peripheral neuropathy and sarcopenia significantly impact physical function in childhood ALL survivors, with impaired muscle strength emerging as a key determinant of mobility limitations. These findings emphasize the importance of targeted interventions, particularly strengthening exercise, to improve functional outcomes in this vulnerable population. Future research should focus on developing evidence-based rehabilitation strategies to enhance long-term survivorship care. Clinical impact Evaluation of muscle strength, lean mass, and gait performance may facilitate early identification of survivors at risk for functional decline and premature aging.