INTRODUCTION: Patients with cancer may have many complications involving their psychosomatic systems, such as sleep disturbance, depression, and anxiety. Thus, many research studies were conducted to reduce these complications. Zolpidem, as a short-term non-benzodiazepine treatment of insomnia, and melatonin as a chronobiological functionregulatory hormone, are commonly used for improving sleep quality. This randomized clinical trial aims to compare the effects of zolpidem and melatonin on sleep quality, depression, and anxiety in patients with colorectal cancer. METHODS: In this single-blinded trial, 90 patients with colorectal cancer undergoing chemotherapy who had obtained a score of 5 or higher on the Pittsburgh Sleep Quality Index (PSQI) were randomly divided into two groups (n=45). One group was treated with 10 mg zolpidem at bedtime, and the other group received 6 mg melatonin at bedtime for 30 days. PSQI on weeks 0, 4, 8, Groningen sleep quality scale, Hamilton rating scale for depression, and Hamilton anxiety rating scale questionnaires were performed to assess patients on weeks 0, 4, and 8. The outcome was then analyzed, and P≤0.05 was considered statistically significant. RESULTS: Both zolpidem and melatonin had significant impacts on sleep quality in week 4 (P<0.05). After stopping the treatments, the conditions were noticeably reversed on week 8 (P<0.05). Zolpidem and melatonin were relatively similar in affecting sleep duration, latency, efficiency, and disturbance. None of the two study medications had any considerable influence on anxiety and depression. CONCLUSION: Melatonin and zolpidem are promising agents for treating sleep complications and, to some extent, depression, and anxiety in cancer patients, according to the present study. However, further clinical trials are recommended to confirm the results of this study.