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Background and Aims Catheter-related bladder discomfort (CRBD) is a distressing postoperative complication following indwelling urinary catheterization. The objective of this study was to evaluate the efficacy and tolerability of pre-emptive oral melatonin in preventing CRBD in patients undergoing transurethral resection of the prostate (TURP) in terms of postoperative pain, sedation, rescue analgesics requirement, and patient/surgeon satisfaction.Methods Seventy adult males aged between 40–75 years undergoing TURP with intraoperative urinary catheterization were randomised to Group M (to receive Melatonin 5 mg oral melatonin night before and morning of surgery) and Group D (to receive vitamin C as placebo). The primary outcome was assessment of the incidence of CRBD at 24 h. The secondary outcomes were assessment of severity of CRBD, postoperative pain, sedation, number of rescue analgesics, patient/surgeon satisfaction, and adverse effects if any. Independent t test was used to compare normally distributed quantitative data, while Mann-Whitney U test was conducted to analyse non normally distributed quantitative variables. The Chi squared test or Fisher’s exact test was employed to assess the association between categorical variables. Tests were two-tailed with a significance level set at p <0.05.Results The incidence of CRBD was significantly lower in Group M as compared to Group D at 2 h (p=0.005), 4 h (p=0.004), 12 h and 24 h (p< 0.0001). The severity of CRBD was less in Group M at all time intervals (p< 0.001). The visual analogue scale (VAS) scores were lower in Group M at 2, 8, 12 and 24 h ( p<0.0001) and fewer patients required rescue analgesics in group M as compared to group D (p=0.0006). Patient satisfaction was higher with melatonin (p=0.121), with a trend toward higher surgeon satisfaction (p=0.064). Melatonin was well tolerated with no significant sedation differences.Conclusions Preemptive oral melatonin effectively reduces CRBD incidence/severity, enhances postoperative comfort, without sedation or adverse effects.