Despite the progress of the development of antimicrobial therapeutics, the whole world is still under pressure of several microbial diseases. Antimicrobial drug development is therefore considered as one of the most practicable research works at present time. Even most of the pharmaceutical companies are investing to develop better therapeutic solutions against the life-threatening infectious diseases caused by Mycobacterium tuberculosis, Helicobacter pylori, Vibrio cholerae, Entamoeba histolytica, Plasmodium falciparum and many others. These microbial pathogens are not only a curse for human health but also a result in huge economic losses by affecting the health of economically important animals like poultry, cattle and other livestock. Considering the urgency, several effective antibiotics have been developed to combat microbial diseases and are available in the market. However, emergence of resistance against these drugs due to the maluses has created an alarming situation. In this scenario, the use of bioactive noble metal nanoparticles (silver, gold and platinum nanoparticles) has shown better therapeutic efficiency in terms of low treatment dose, less toxicity and absence of microbial resistance. Moreover, the use of several surface modifiers, coating and stabilizing agents resulted in enhancement of the bioactivity, rapid delivery and controlled drug release, improvement of biocompatibility and cytotoxicity. In this chapter, we have presented a comprehensive overview on the antimicrobial efficacy of noble metal nanoparticles along with the mechanistic insights behind their activity at the cellular and molecular level. Nabarun Chandra Das, Bishnupada Roy, and Ritwik Patra have been contributed equally to this chapter.