Introduction Transitioning out of professional football is a challenging time in most players' lives. During these preretirement and postretirement years, professional footballers may struggle with their mental, musculoskeletal, neurocognitive and cardiovascular health. Currently, longitudinal data about these health conditions are lacking. This article presents the design of a prospective cohort study with the primary aim of gathering epidemiological evidence about the onset and course of mental, musculoskeletal, neurocognitive and cardiovascular health conditions in professional footballers during their preretirement and postretirement years and evaluating the associations between risk indicators and the health conditions under study in these players. Methods and analysis An observational prospective cohort study with repeated measurements over a follow-up period of 10 years will be conducted among at least 200 professional footballers (male; 27 (±1) years old). Mental health will be explored by assessing symptoms of distress, anxiety, depression, sleep disturbance, alcohol misuse, drug misuse and disordered eating. Musculoskeletal health will be explored by assessing severe joint injury and related surgery, clinical and radiological osteoarthritis, and joint function (hips, knees and ankles). Neurocognitive health will be explored by assessing the concussion, brain structure and functioning, and neurocognitive functioning. Cardiovascular health will be explored by assessing blood pressure, lipid profile and ECG abnormalities. Ethics and dissemination Ethical approval for the study was provided by the Medical Ethics Review Committee of the Amsterdam University Medical Centers. The results of the study will be submitted to peer-reviewed journals, will be presented at scientific conferences and will be released in the media (postpublication). Trial registration number The Dutch Trial Registry (Drake Football Study NL7999).