BACKGROUND: Given the significant impact of depression, sexual function, and health-related quality of life (HRQOL) in women with Polycystic Ovarian Syndrome (PCOS), it is crucial to identify scientifically supported interventions that enhance these outcomes and thereby promote HRQOL. AIM: The present study aimed to assess the effect of adjutant administration of Sildenafil plus Melatonin on psycho-sexual status in PCOS women undergoing Metformin in an Iranian population. METHODS: This study was a randomized clinical trial. 216 Eligible women were assigned to four groups including Sildenafil plus Metformin, Melatonin plus Metformin, Melatonin plus Sildenafil and Metformin, and Metformin alone. The duration of intervention was 3 months. OUTCOMES: The Female Sexual Function Index, Hospital Anxiety and Depression Scale and modified PCOS health-related QOL questionnaire were used to evaluate sexual function, severity of depression and HRQOL, respectively. RESULTS: Based on the results of the present study, statistically significant improvement was found in menstrual cyclicity, sexual function (desire and arousal), HRQOL concerning menstrual and emotional aspects and severity of depression between the groups before and after the intervention in Sildenafil plus Melatonin compared to other groups after 3 months (P < 0.05). CLINICAL IMPLICATIONS: The present research determined administration of Sildenafil plus Melatonin enhances menstrual cyclicity status, mental well-being, sexual function, and HRQOL in women with PCOS who undergoing Metformin treatment. STRENGTHS & LIMITATIONS: The current research possesses several strengths, notably its adherence to the rigorous standards of a randomized controlled trial with well-defined initial inclusion criteria. In addition, this questionnaire is based on the previously ratified tools used. A robust sample size was maintained, enhancing the statistical power of the analysis. However, all the sample participants were sourced from a university referral clinic. Additionally, due to cultural norms, every participant in this study was married. Lastly, the absence of a post-intervention follow-up period is a notable gap; such a period could help determine the duration of the clinical effects or assess if ongoing treatment with Sildenafil plus Melatonin is necessary to sustain these effects. CONCLUSIONS: Findings from this initial randomized controlled trial indicate that a 12-week administration of Sildenafil plus Melatonin could enhance menstrual cyclicity status, reduce depression severity, and sexual function as well as HRQOL in women with PCOS who undergoing Metformin.