The world’s sensitivities about having Premarital Sexual (PMS) relationships, regardless of marriage, are changing. The lack of a coherent program in sex education has led to the establishment and formation of misconceptions and misinformation among adolescents. The purpose of this questionnaire-based study is to prepare a Comprehensive Sex Education (CSE) protocol for psycho-religious-based CSE and determine its effectiveness in reducing the tendency toward PMS. This research was a quasi-experimental study with a pretest-posttest control group design. The sample includes all 15 to 18-year-old girls in Mashhad who participated in this workshop voluntarily in 2019-2020. The participants were assigned randomly to either the test or control group (15 individuals per group). To collect data, the Premarital Relationship Attitude Questionnaire (PRAQ) (Mobredi et al., 2018) was used. The test group, along with regular medical care, received CSE for 9 weekly sessions of 100 minutes (5 hours per week) (from September up to the end of November 2019) in the private clinic of the psychology of Mashhad. The control group received only regular medical care in this period. Participants in both groups responded to the PRAQ before intervention (pretest) and immediately after the intervention (posttest). Results of analysis of covariance showed that after statistically controlling the effect of the pretest, a significant difference was found between the test and control group in terms of the PMS (P < 0.05). Moreover, the effectiveness of the variables of the method of obtaining information, the birth order, and the quality of family relationships on the tendency toward PMS was confirmed. These findings suggest that the use of psycho-religious-based CSE has reduced the tendency toward PMS in girls.