Norgestrel, a widely used synthetic progestin, may threaten marine ecosystems, although research on its impact is limited. In this study, marine medaka (Oryzias melastigma) embryos were exposed to combinations of two salinity levels (30 ‰, 10 ‰) and three norgestrel concentrations (0, 3.69, 17.96 ng/L; 0, 3.76, 18.41 ng/L) for 90 days until adulthood, and the effects on growth, sex differentiation, reproduction, liver health, and antioxidant responses were evaluated. Results showed that low salinity reduced growth, whereas norgestrel did not significantly affect growth at either salinity. However, high norgestrel concentration reduced egg production, induced a male-biased sex ratio, and caused histopathological changes such as fibrosis and reduced sperm count in testicular tissue, irregular oocyte morphology, and even the presence of bisexual structures at both salinities. In females, norgestrel lowered FSH, LH, and T levels but increased E2 and 11-KT across both salinity conditions. Norgestrel under low or high salinity altered gene expression in gonads: it up-regulated erα, erβ, lhr, star, cyp11a, 3βhsd, cyp17a1, and cyp19a genes in females, but down-regulated erα, erβ, fshr, lhr, star, cyp11a, 3βhsd, cyp17a1, 17βhsd, cyp11b, cyp19a and pgr genes in males. In male liver tissues, norgestrel increased expression of erα, arα, vtg1, vtg2, chgh, and chgl genes under high salinity. These gene transcriptional alteration and reproductive hormonal imbalances, ultimately reduced egg production. Norgestrel also induced liver damage at both salinities, more severely in females. Additionally, norgestrel lowered CAT activity in ovaries, suggesting ovarian damage. Two-way ANOVA revealed a significantly interaction between salinity and norgestrel, indicating that salinity modulates norgestrel's toxic effects on sexual differentiation, egg production, reproductive hormones, gene transcription, and oxidative stress. In contrast, norgestrel's effects on growth, gonadal and hepatic histology were independent of salinity. Principal component analysis (PCA) further validated the overall disruptive effects of salinity and NGT, showing clear separation between treatment groups driven by HPG axis-related genes, reproductive hormones, and growth traits. This study highlights the reproductive endocrine-disrupting potential of norgestrel in coastal environments with variable salinity.