Background: Pain accompanying office hysteroscopy, possibly aggravated by urogenital atrophy, is the most common reason for its discontinuation. The aim was to evaluate the effectiveness of vaginal estriol and hyaluronic acid to facilitate the office hysteroscopy in peri and postmenopausal women. Methods: A prospective cohort study involved women aged 45–90 years subjected to office hysteroscopy. Women were assigned to three study arms: (A) 0.5 mg of estriol in vaginal cream twice daily for 10 days pre-procedure, (B) 5 mg of hyaluronic acid in vaginal gel twice daily for 10 days pre-procedure, (C) no medication. The following endpoints were compared: pain accompanying the procedure, need for cervical dilation, time of cervical passage, incidence of severe urogenital atrophy, and vaso-vagal reaction. Results: There were no significant differences between the arms in terms of pain intensity during (p = 0.93) and after the procedure (p = 0.17), need for cervical dilation (p = 0.5), cervical passage time (p = 0.1), severe urogenital atrophy (p = 0.15), and vaso-vagal reaction (p = 0.29). Conclusions: Despite unfavorable conditions in peri and postmenopausal women, cervical preparation in the above regimens did not seem to bring clinically significant benefits. Clinical Trial Registration: The study was registered under the number NCT05783479 in the Protocol Registration and Results System database (https://clinicaltrials.gov/). The database used for the study was made available in Harvard Dataverse (https://doi.org/10.7910/DVN/HSWURD).