To evaluate the effects of a 24/4 regimen combined oral contraceptive (COC) containing 1.5 mg 17β-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) compared to on-demand nonsteroidal anti-inflammatory drugs (NSAIDs) on women affected by endometriosis-associated chronic pelvic pain (the primary end point) and their quality of life (QoL) and sexual function (the secondary end points). Ninety-nine women on E2/NOMAC constituted the study group; and 63 women on NSAIDs constituted the control group. The visual analogic scale was used to measure the levels of pelvic pain, dysmenorrhea, and dyspareunia. To assess their QoL, sexual function, and sexual distress, the Short Form-36 (SF-36), the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS) were used, respectively. The study included two follow-ups at 3 and 6 months. Improvement in chronic pelvic pain was observed in the study group at both the 3- and 6-month follow-ups ( < 0.001). SF-36, FSFI, and FSDS had a similar trend at the 3- and 6-month follow-ups ( < 0.001). Women on NSAIDs did not report any reduction in pain symptoms or improvement in QoL ( ≤ 0.4). However, they had a limited improvement of their FSFI and FSDS ( < 0.001). The improvement of the pain symptoms, QoL, FSFI, and FSDS, was more evident in women on E2/NOMAC than in those on NSAIDs, when the study group and control group values were compared at the 3- and 6-month follow-ups ( < 0.001). Women on E2/NOMAC COC showed a better reduction of endometriosis-associated chronic pelvic pain and an improvement of their QoL and sexual activity than those of the women on NSAIDs.