Serine protease account for about 40% of all protease in human and forms the largest group of proteases. They are crucial in health; however, unlimited protease activity can lead to disease conditions when checkpoints fail during defined physiological conditions. As a counter, serine protease inhibitors are present that can control the unbalanced proteolytic activity of serine proteases. They allow for achieving a state of equilibrium between proteolytic activity and its inhibition that further prevent comorbidities. Regarding this, several sources were initially evaluated for different types of serine protease inhibitors, followed by a study of their structures and active sites involved in their action. The recent focus is on designing new compounds acting as serine protease inhibitors with better selectivity, inhibition, and efficiency. This paves the way for more potential as a therapeutic agent in the management of diseases.