Objective: Despite the fact that cancer patients are highly susceptible to drug-related problems due to the effects of cytotoxic agents, data are limited due to a lack of studies on those patients. Hence, we aimed to investigate drug-related problems among patients diagnosed with colorectal cancer. Method: A registry-based cross-sectional study was conducted on colorectal cancer patients at the Felege Hiwot Comprehensive Specialized Hospital. Socio-demographic and disease-related characteristics, treatment regimens, and drug-related problems were recorded by reviewing medical records. Standard guidelines, protocols, and databases were used to evaluate the occurrence of drug-related problems and the severity of adverse drug reactions. For the analysis, Stata version 16/MP for Windows was used. Logistic regression analysis was employed to investigate the potential-associated factors of drug-related problems. A p-value ⩽ 0.05 was used to declare the statistical significance of each independent variable. Results: A total of 150 colorectal cancer patients were included, with a mean age of 51.4 ± 13.8 years. About 30% and 41.3% had stage II and stage III cancers, respectively. About three-quarters (73.8%) of the patients were given 5-fluorouracil-based combination regimens. The prevalence of drug-related problems was found to be 48.7%, with a mean of 2.12 ± 0.93 drug-related problems. In the Felege Hiwot Comprehensive Specialized Hospital, drug–drug interactions and adverse drug reactions were the most prevalent drug-related problems, which accounted for 50 (32.7%) and 49 (32%) cases, respectively. Being elderly (>50 years old) ( p = 0.013), having co-morbidity ( p = 0.001), and being on five or more medications ( p = 0.002) were independent predictors of drug-related problems. Conclusion: Fluorouracil-based chemotherapy was the most frequently used treatment regimen. Almost, half of the colorectal cancer patients had one or more drug-related problems. About one-third of patients had adverse drug reactions and drug–drug interactions. Furthermore, age, co-morbidity status, and the number of medications used were significantly associated with drug-related problems. Clinical pharmacy services should be implemented to optimize drug therapy because the majority of colorectal cancer patients have one or more drug-related problems.