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Antibiotics are the most magnificent discovery of 20th century that have saved millions of lives from infectious diseases. Microbes have developed acquired antimicrobial resistance (AMR) to many drugs due to high selection pressure from increasing use and misuse of antibiotics over the years. The transmission and acquisition of AMR occur primarily via human–human interface both within and outside of the healthcare facilities. A huge number of interdependent factors related to healthcare and agriculture govern the development of AMR through various drug resistance mechanisms. The emergence and spread of AMR from the unrestricted use of antimicrobials in livestock feed has been a major contributing factor. The prevalence of AMR bacteria has attained its incongruous level worldwide and threatening global public health as silent pandemic, necessitating urgent intervention. Therapeutic options of AMR bacterial infections are limited resulting in significant morbidity and mortality with high financial impact. The paucity in discovery and supply of new novel antimicrobials to treat life-threatening AMR infections stands in sharp contrast to demand. Immediate interventions to contain AMR include surveillance and monitoring, minimizing over the counter antibiotics and antibiotics in food animals, access to quality and affordable medicines, vaccines and diagnostics, and enforcement of legislation. An orchestral collaborative action within and between multiple national and international organizations are required urgently, otherwise, a post-antibiotic era can be a real possibility than an apocalyptic fantasy for the 21st century. This narrative review highlights on the basis, mechanisms and factors in microbial resistance and key strategies to combat antimicrobial resistance.