Purpose: The aim of present study was to study the effect of osteopathic manipulation on pain relief and quality of life improvement in hospitalized oncology geriatric patients. Methods: A nonrandomized controlled clinical trial was performed in the Oncology Rehabilitation Unit, Milan, Italy, from September 2015 to March 2016. Twenty-three older cancer patients were enrolled and allocated in 2 experimental groups: the study group (OMT group, N = 12) underwent osteopathic manipulative treatment in addition to physiotherapy, and the control group (PT group, N = 12) underwent only physiotherapy. At enrollment (T0), 24 recruited oncology patients completed the sociodemographic forms and were evaluated for pain intensity and quality of life by an external examiner. All patients were revaluated every week (T1, T2, T3, and T4) for pain intensity and at the end of the study treatment (T4) for quality of life. A standard level of significance was set at α < .05. Results: The 2 groups did not significantly differ in age (P = .682), body mass index (P = .413), or gender (P = 1). The osteopathic manipulative treatment added to physiotherapy produced a significant reduction in Numeric Rating Scale (NRS) scores both at T2 (P = .004) and T4 (P = .002). The difference in quality of life improvements between T0 and T4 was not statistically significant. NRS improved in the PT group at T4. Between-group analysis of NRS and quality of life with the Mann-Whitney test did not show any significant difference between the 2 treatments. Conclusions: Our study showed a significant improvement in pain relief and a nonsignificant improvement in quality of life in hospitalized geriatric oncology patients during osteopathic manipulative treatment. Trial Registration: Protocol registered on Clinicaltrials.gov (NCT03142386).