Platelets play a pivotal role in processes such as hemostasis, thrombosis, and immune responses, positioning them as key contributors to various pathological conditions, including cardiovascular diseases, cancer, infections, and genetic disorders such as sickle cell disease. The intricate biological mechanisms involving platelets are highly complex and challenging to replicate in vitro, underscoring the necessity of in vivo models. Since the 1990s, the use of both genetically modified and nongenetically modified animal models, particularly mice, has significantly expanded. Simultaneously, advancements in computer science and technology have enabled the development of intravital microscopy techniques, allowing researchers to study platelet functions in real time within living systems. The primary advantage of these models is their ability to mimic physiological conditions, incorporating the full range of cellular and subcellular interactions that influence pathology. This provides invaluable insights into the complex roles of platelets in vivo, offering a realistic context for understanding their behavior in health and disease. However, many of these models rely on artificial methods to replicate specific pathological conditions, which may introduce limitations and create discrepancies between the model and actual human pathophysiology. This chapter aims to comprehensively review the literature on the various mouse models used to study platelet function in thrombotic and non-thrombotic diseases, highlighting their strengths and limitations. By evaluating these models, the review seeks to shed light on their contributions to platelet research and their relevance to understanding human diseases.