The pineal hormone melatonin plays a major role in numerous physiological functions such as circadian sleep-wake rhythm, mood, immunity, and reproduction. Patients on hemodialysis (HD) frequently suffer from sleep and psychiatric disturbances. The aim of this study is to assess the effect of exogenous oral melatonin in HD patients regarding sleep disturbances, depression, and anxiety alongside the quality of life (QoL). In this randomized double-blind placebo-controlled study, 60 stable HD patients suffering from sleep disorders [according to Pittsburgh sleep quality index (PSQI) equal or more than 5] were randomized to receive melatonin 3 mg at 10 pm every night or placebo tablets for three months. Routine laboratory investigations were done, moreover, patients were asked to fill the following six questionnaires at the beginning of the study and after three months of treatment; PSQI, Epworth Sleepiness Scale (ESS), and the Insomnia Severity Index (ISI) to assess sleep disorders, assessment of depression by Hamilton Depression Rating Scale (HDRS), assessment of anxiety by Hamilton Anxiety Rating Scale (HARS), and assessment of QoL using Quality of Life Index-dialysis version (QLI). This study showed a significant improvement in serum calcium, low-density lipoprotein level (P ≤0.005), and scores of HDRS, HARS, and total QLI in the melatonintreated group (P ≤0.001, 0.001, and 0.002, respectively). Moreover, there was a highly significant improvement in sleep disorders in melatonin-treated patients regarding total score of PSQI, ISI, subjective sleep quality, and daytime dysfunction (P ≤0.001), also regarding sleep duration, latency, and disturbances (P ≤0.05). However, there was no significant difference in sleep efficiency and ESS scores. Exogenous melatonin treatment was well-tolerated, safe, and efficient in improving sleep disturbances, depression, anxiety, and QoL in HD patients.