To elucidate the endocrine-disrupting mechanisms and sex-dependent responses of organophosphate flame retardants (OPEs), tris(1-chloro-2-propyl) phosphate (TCPP) and resorcinol bis(diphenyl) phosphate (RDP), adult zebrafish (Danio rerio) were employed as a model organism. Exposure experiments were conducted at two concentrations corresponding to 1% (400 μg/L) and 1‰ (40 μg/L) of the 96h median lethal concentration (LC₅₀). The results showed that neither TCPP nor RDP exposure caused significant changes in body condition factor, brain somatic index (BSI), or gonad somatic index (GSI) in either female or male zebrafish. However, acetylcholinesterase (AChE) activity was significantly inhibited in all exposed groups by 7.80%~31.31%(P<0.01), with females exhibiting greater sensitivity to TCPP. Meanwhile, malondialdehyde (MDA) levels were significantly elevated (34.37%~166.25%), whereas glutathione (GSH) contents were markedly reduced (29.51%~58.64%) indicating that both TCPP and RDP induce oxidative stress in zebrafish. Exposure to TCPP and RDP significantly disrupted the function of the hypothalamic-pituitary-thyroid (HPT) axis, as evidenced by decreasing triiodothyronine (T3) levels and increasing thyroxine (T4) levels, with more pronounced effects observed in females (P<0.01, P<0.05). Gene expression analysis further revealed that TCPP and RDP significantly downregulated the HPT axis-related genes crh and tshβ in females (P<0.05), whereas no significant alterations were detected in males, confirming a clear sex-dependent disruption of the HPT axis by these OPEs. In addition, TCPP and RDP exposure disturbed sex hormone homeostasis in zebrafish. In males, testosterone levels were significantly increased, while estradiol levels were markedly decreased (P<0.001). Consistent with these hormonal alterations, the expression of cyp19a1a, a key gene involved in the hypothalamic-pituitary-gonadal (HPG) axis, was significantly downregulated, inhibiting the conversion of testosterone to estradiol. This disruption may impair spermatogenesis and sperm motility in males zebrafish. Overall, TCPP and RDP exposure induced pronounced endocrine disruption via interfering with both the HPT and HPG axes, with distinct sex-dependent effects. This study underscores the importance of considering sex differences in the toxicological evaluation.