BACKGROUND Polypharmacy is associated with increased risks of adverse outcomes in people with cancer and medicine use evolves over the course of the disease trajectory. We estimated the prevalence of polypharmacy in people with colorectal cancer (CRC), stratified by extent of disease spread at diagnosis, during each year from one year prior to five years following diagnosis and determined factors associated with polypharmacy at diagnosis and two and five years post-diagnosis. METHODS Our retrospective cohort study used linked administrative health records from New South Wales (NSW), Australia to examine medicine use in all NSW residents ≥18 years diagnosed with CRC between 2013-2017. We defined polypharmacy as concomitant exposure to ≥ 5 medicines, excluding antineoplastics, during at least one 90-day quarter in each year from diagnosis. We used logistic regression to examine associations between polypharmacy and relevant factors. RESULTS Of 19,056 people diagnosed with CRC, 6,797 (35%), 8,482 (45%), and 3,777 (20%) were diagnosed with localised, regional, and metastatic disease, respectively. Within these groups, 74%-79% experienced polypharmacy at any time during the study period; with nearly 50% experiencing polypharmacy two through five years from diagnosis. Age (≥70 years), female sex, comorbidities, colon cancer diagnosis, and socioeconomic disadvantage were associated with increased likelihood of polypharmacy at all landmarks. CONCLUSIONS Polypharmacy is highly prevalent among Australians with CRC. For those treated with curative intent, higher polypharmacy rates are concerning, indicating excess morbidity and impaired quality of life among survivors cured of cancer but who may continue to experience poorer health than the general population.