Coagulation disorders, such as excessive bleeding or thrombosis, present significant health challenges. Vitamin K-dependent proteins (VKDPs), including coagulation and anticoagulation factors, are essential for maintaining the coagulation homeostasis due to their key roles in the coagulation cascade. Therefore, VKDPs have become significant targets for regulating coagulation homeostasis, and various strategies have been developed, primarily including small molecule drugs and nanomaterials. This review presents the summary of these strategies, focusing on the mechanisms, effectiveness and limitations. It first discusses the pivotal role of VKDPs in the coagulation cascade, followed by an in-depth analysis of how small molecule drugs and nanomaterials to regulate hemostasis through interfering with VKDPs. Furthermore, this review addresses the challenges faced in the current approaches and potential future research directions. We hope this review will contribute to advancing the development of novel methods for modulating coagulation homeostasis through VKDP interference.