Older patients with cancer are underrepresented in trials investigating the effect of exercise therapy. The aim of this systematic review was to investigate the effect of exercise therapy during medical antineoplastic treatment in older patients (≥ 65 years) with cancer. A systematic review following the Cochrane guidelines was performed. Randomized controlled trials were identified through a systematic literature search in MEDLINE, EMBASE, CENTRAL, and CINAHL up to December 2019. Study selection was performed independently by two reviewers. Four randomized controlled trials published between 2014 and 2019 were included comprising a total of 412 participants. Most participants were diagnosed with breast, prostate or colorectal cancer. The studies were characterized by large differences in design, interventions and outcomes, which prevented meta-analyses. The interventions ranged from 4 weeks to 12 months and involved both supervised and unsupervised exercise programs. Some evidence of beneficial effects from the interventions were documented on physical function, muscle strength, physical activity and cognitive function. No evidence of effects was found for health-related quality of life, aerobic capacity, body composition, cancer-related symptoms and side effects, or for any clinical outcomes. No adverse events were reported. Exercise therapy seems to be safe and feasible in older patients with cancer. However, due to a limited number of studies, small sample sizes and heterogeneity across study design, the effects of exercise in older patients with cancer receiving medical antineoplastic treatment are inconclusive.