Introduction Many cancer patients experience high levels of anxiety during chemotherapy, which can negatively impact their mental health and their physiological, emotional, and spiritual well-being. Different complementary therapies aim to attenuate these effects, including music therapy. Although there is preliminary evidence on the positive effects of music therapy and music-based interventions in chemotherapy wards, few studies report live group interventions delivered by accredited music therapists. Objective To determine the effect of a single live group music therapy intervention on state anxiety and well-being levels of adult cancer patients during chemotherapy. Methodology This study protocol follows the SPIRT guidelines and reports a two-arm multicenter randomized clinical trial (RCT). The intervention group will receive standard care + a live group music therapy session and the control group will receive standard care only. The primary outcome is state anxiety, measured with the six-item State-Trait Anxiety Inventory (STAI-6). The secondary outcome is well-being, measured with the Well-being Numerical Rating Scales (WB-NRSs). The scales will be applied before and after each intervention. Sample size calculation resulted in a total of 102 participants. Conclusions This study seeks to contribute to the improvement of psycho-emotional health and well-being of cancer patients during chemotherapy. It is the first multi-center RCT on music therapy with cancer patients in [country, de-identified for peer review] and aims to gather knowledge about music’s role to improve patients’ mental health during acute treatment. Trial Registration clinicaltrials.gov (NCT06577324, submission date August 21st, 2024).