Background: High risk sexual behavior (HRSB) contributes significantly to sexually transmitted diseases (STIs) and unwanted pregnancy. This study was aimed at assessing effects of interactive educational intervention, on knowledge, attitude and practice of safe sexual behavior, among sexually active in-school adolescent girls in Calabar, Nigeria. Methods: Quasi-experimental study design was used, with recruitment of one hundred and twenty (120) respondents in two senior secondary schools, comprising sixty (60) each, in groups 1 (control) and 2 (intervention). Group 2 received 2-hour daily, 3-day face-to-face educational teachings on sexual health. Outcome measures assessed at baseline, immediate post-intervention and 12-weeks follow-up, were level of knowledge, attitude and sexual health behavioral practices, with maximum scores of 62, 55 and 35, respectively. Independent t-test was used as inferential statistic, with p-value set at 0.05. Result: Mean age was 17.2 ± 1.1 years (14-19 years). At baseline, comparing groups 1 and 2, there was no significant difference in level of knowledge (24.7 vs. 26.1), attitude (33.7 vs. 32.2) and practice (23.8 vs. 24.7) of sexual health. Compared with group 1 (control), respondents in group 2 (intervention) had significantly higher level of knowledge of sexual health at immediate post-intervention (25.5 vs. 56.4, p<0.05) and 12-weeks follow-up (24.0 vs. 50.8, p<0.05). There was no significant difference in practice scores between the groups comparing these periods (p>0.05). Conclusion: Interactive educational intervention, is effective in improving knowledge of sexual health among sexually active adolescent girls. Concerted effort at establishing and sustaining school-based sexual health education should be encouraged.