Objectives <p>To assess the safety and efficacy of misoprostol administration before hysteroscopy in peri- and post-menopausal women.</p> Search strategy <p>Screening of databases from inception to July 2023 using the keywords related to “Misoprostol” AND “Hysteroscopy” AND “Menopause”.</p> Selection criteria <p>Eleven studies (1029 participants) were included in our quantitative and qualitative analysis. The dose of misoprostol ranged between 200 and 1000 ug. The routes of misoprostol administration were oral, rectal, sublingual, and vaginal. The timing of administration before the procedure ranged between 2 hours and 12 hours in 8 studies.</p> Data collection and analysis <p>The data extracted included the publication year, the study settings, blinding, sample size, participants inclusion and exclusion criteria, misoprostol administration (dose, route and timing), outcome parameters including difficult dilatation or the need for dilatation, time needed for cervical dilatation, preoperative cervical width, Side effects, complications and intraoperative and postoperative pain score, presence and timing of trial registration and any funding details.</p> Main Results <p>Difficult cervical dilatation or the need for further cervical dilatation was reported in 8 studies with 738 participants. It has an OR effect estimate of 0.36 with 95% CI of 0.14-0.93 (<i>P</i> =0.04).</p> <p>The time needed for cervical dilatation was reported in 2 studies with 136 participants. It has a mean difference effect estimate of -15.59 with 95% CI of -20.25, -10.93 (<i>P</i> &lt;0.001).</p> <p>Preoperative cervical width was reported in 7 studies with 659 participants. It has a mean difference effect estimate of 0.51 with 95% CI of -0.52, 1.53 (<i>P</i> =0.33).</p> <p>The occurrence of adverse effects was reported in 7 studies with 715 participants. It has an OR effect estimate of 2.66 with 95% CI of 0.99-7.13 (<i>P</i>=0.05).</p> <p>Analysis of specific side effects showed that nausea, diarrhea, fever, vaginal bleeding and preoperative pain sensation were estimated in 3 (290 women), 5 (488 women), 2 (176 women), 5 (430 women) and 5 (464 women) studies and their OR effect estimate [95%CI] were 2.50 [0.69, 9.01], 3.59 [0.72, 17.76], 6.29 [0.74, 53.59], 2.17 [0.59, 7.94], and 2.63 [1.20, 5.79] respectively (<i>P</i> &gt;0.05 except in pain <i>P</i> =0.02).</p> <p>The prevalence of intraoperative complications was reported in 9 studies with 761 participants. It has an OR effect estimate of 1.71 with 95% CI of 0.79- 3.70 (<i>P</i> =0.17).</p> Conclusion <p>This systematic review confirmed beneficial effects of misoprostol on the time needed for cervical dilatation (low evidence), the number of cases with difficult cervical dilatation and the increase in side effects.</p> Trial&#xa0;registration number <p>CRD42023438429</p>