Bisphenol A (BPA) has been strictly regulated worldwide due to its well-documented adverse health effects, prompting the widespread use of structural analogs such as bisphenol AF (BPAF) and bisphenol fluorene (BHPF). Emerging evidence shows that these substitutes also exhibit estrogenic activity, challenging their presumed safety. However, the molecular mechanisms underlying their modulation of estrogen receptors (ERs) remain largely unknown. Addressing this gap is critical for accurate risk assessment and the development of safer alternatives. Herein, we employed computational toxicology approaches to elucidate the interaction mechanisms of BPAF and BHPF with ER alpha (ERα), a central regulator of endocrine function and breast cancer progression. Our results showed that BHPF displays the greatest estrogenic potency among the tested compounds. Molecular interaction analyses revealed that hydrophobic interactions, especially the van der Waals force, rather than hydrogen bonding, predominantly govern the binding of the two bisphenol derivatives (BPs) to ERα. Notably, the rigid fluorenyl ring structure of BHPF markedly enhances van der Waals interactions, resulting in more stable ER binding and suggesting potential for high biological retention and cumulative risk. Consistently, toxicological assessments indicated that BHPF poses elevated health risks to the lungs and gastrointestinal system. By contrast, BPAF, with its flexible scaffold, exhibited more diverse binding interactions. It exhibits stronger organ-specific toxicity, notably affecting the cardiovascular system and kidneys. This study provides molecular-level insight into the binding mechanisms of BPs with ERα, offering theoretical support for understanding their potential endocrine-disrupting effects and informing environmental health risk assessments.