BACKGROUND: The increase in the survival of oncology patients include multiple side effects as cancer-related asthenia and dyspnea, which represents a serious health problem. An implementation of the conventional clinical practice, developed through multimodal physical exercise and functional rehabilitation program intervention, may be useful in controlling dyspnoea. This study aims to evaluate the effects of a multimodal exercise and functional rehabilitation program on fatigue, pain, functional capacity, and quality of life in cancer patients with cancer-related asthenia. METHODS: This is a protocol for an experimental, prospective, randomised study using a parallel, fixed assignment scheme, with an experimental group and a control group in patients from the oncology hospitalisation unit at the Salamanca University Hospital Complex in Spain, using consecutive sampling to select 50 participants with oncological asthenia who are hospitalised at the time of inclusion. After the baseline evaluation, the participants will be randomised into two groups. Both groups will receive standard clinical practice care and the normal health education program at discharge, but in addition, the participants assigned to the experimental group will also complete a multimodal exercise and functional rehabilitation program lasting one month. The primary outcomes will be basic activities of daily living (Barthel Index) and degree of asthenia (FACT-An scale). Additionally, physical performance will be evaluated with the Short Physical Performance Battery (SPPB), as will the attention and executive functions (Trail-Making Test), fear/avoidance of movement (TAMPA scale), pain (VAS scale), and body composition (waist, hip, brachial, thigh, wrist, and ankle circumferences). DISCUSSION: The results of this study may be translated to clinical practice, incorporating a specific autonomy recovery programme into comprehensive rehabilitation programmes of care for cancer patients with asthenia. The current study addresses to improve the conventional clinical practice by proposing a multimodal physical exercise and functional rehabilitation program intervention, which will be implemented by an interdisciplinary team, to try to improve the autonomy of cancer patients with cancer-related asthenia. TRIAL REGISTRATION: ClinicalTrials.gov; ID: NCT04761289. (February 18, 2021).  https://clinicaltrials.gov/ct2/show/ NCT04761289.