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Increased incidences of multidrug-resistant (MDR) microorganisms has become a global health concern for humans, animals, and agriculture. The advent of newer resistance mechanisms evolving in microorganisms at a high rate compared to the treatments available urges the need to understand its origin and reservoirs. The expanded use of antimicrobial drugs, inefficient diagnosis as well as broad use in agriculture and veterinary contributes to the emergence of resistance in microorganisms. Presently, almost all infectious agents (bacteria, fungi, and viruses) have developed MDR. About 7 lac people die of bacterial resistance to antibiotics every year, with an estimated ~10 million deaths by 2050. Similarly, MDR arising in pathogenic fungi like Candida, Aspergillus, or Fusarium to the limited therapeutic options is highly challenging. Bacteria and fungi develop resistance mainly due to biofilm formation, increased efflux pump activity, drug target mutations, drug binding alterations, chromosome abnormalities, and the ability to escape host immune defenses. The co-existence of MDR bacteria and fungi forming biofilms is even much of an alarm in medicinal applications. Apart from these, drug resistance to current antiviral therapeutics has imposed significant risk amidst life-threatening diseases caused due to viruses like HIV and influenza A. Owing to its severity and complexity, we aim to illustrate the detailed mechanism and evolution of MDR in bacteria, fungi, and viruses. We also review different approaches to deal with MDR, emphasizing alternatives, vaccine development, global surveillance programs and stewardship measures to combat resistance.