Protean mesoporous silica nanoparticles (MSNs) are propitious candidates over decades for nanoscale drug delivery systems due to their unique characteristics, including (but not limited to) changeable pore size, mesoporosity, high drug loading capacity, and biodegradability. MSNs have been drawing considerable attention as competent, safer and effective drug delivery vehicles day by day by their towering mechanical, chemical and thermal characteristics. Straightforward and easy steps are involved in the synthesis of MSNs at a relatively cheaper cost. This review reports Stober's synthesis, the first proposed synthesis procedure to prepare micron-sized, spherical MSNs, followed by other modifications later on done by scientists. To ensure the safety and compatibility of MSNs with biological systems, the hemocompatibility evaluation of MSNs using human red blood cells (RBCs) is a widely welcomed exercise. Though our main vision of this overview is to emphasize more on the hemocompatibility of MSNs to RBCs, we also brief about the synthesis and widespread applications of multifaceted MSNs. The strike of different parameters of MSNs plays a crucial role concerning the hemolytic activity of MSNs, which also has been discussed here. The inference is derived by centering some feasible measures that can be adopted to cut down or stop the hemolytic activity of MSNs in the future.