Antimicrobial resistance (AMR) is a major global health issue, particularly in India. Last-resort antibiotics have been weakened by the emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacteriaceae (CRE). This is complicated further by the plasmid-mediated mcr-1 gene, which confers colistin resistance and allows it to spread rapidly through sewage, agriculture, and healthcare systems. The high prevalence of CRE and CRAB in Indian intensive care units, which are frequently caused by NDM and OXA-23-like genes, leads to higher mortality rates and longer hospitalisation. The coexistence of mcr-1 and carbapenemase genes results in pan-drug-resistant “superbugs”. Inappropriate antibiotic use, non-therapeutic use of agricultural colistin, and inadequate infection control are major contributors to antibiotic resistance reservoirs in the environment. India faces challenges in coordinating and enforcing initiatives such as the National Action Plan on AMR, NARS-Net (National Antimicrobial Resistance Surveillance Network), and stewardship programmes. To combat this growing threat, a long-term, comprehensive “One Health” strategy involving strict regulatory enforcement, cross-sectoral collaboration, and effective surveillance is required.