Organ-on-chip (OoC) technology has emerged as a transformative platform for modeling human physiology with enhanced biological relevance compared to traditional in vitro and animal models. By integrating microfluidics, tissue engineering, and biomaterials, OoC systems enable precise control of cellular microenvironments, mechanical cues, and biochemical signaling. This chapter provides an overview of the principles underlying OoC technology and highlights its growing impact on women’s health research, a field historically limited by underrepresentation in clinical trials and inadequate preclinical models. We discuss recent regulatory advances, including the Food and Drug Administration Modernization Act 2.0 and the adoption of New Approach Methodologies, which support the use of human-relevant nonclinical systems. Key applications in drug delivery, diagnostics, tissue engineering, and disease modeling of the female reproductive system are reviewed, with emphasis on ovarian, endometrial, placental, and vaginal OoC platforms. Additionally, the role of biomaterials in enhancing physiological fidelity and enabling dynamic tissue remodeling is examined. Finally, future directions are explored, including multi-organ integration, precision medicine, patient-specific modeling, and positioning OoC technology as a critical tool for advancing translational research and improving outcomes in women’s health.