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Metallo-β-lactamase (MBL)-producing multidrug-resistant (MDR) bacteria have emerged as one of the most critical threats to global public health. These zinc-dependent enzymes, particularly NDM, VIM, and IMP, hydrolyze carbapenems, the last-resort antibiotics for treating severe Gram-negative infections. Unlike serine-β-lactamases, MBLs evade all clinically approved β-lactamase inhibitors, leaving a profound therapeutic vacuum. This review synthesizes evidence from 204 peer-reviewed articles (1970–2026) to examine the molecular diversity, global burden, diagnostic approaches, risk factors, and future directions for MBL-producing pathogens, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. MBL genes are predominantly disseminated via mobile genetic elements (plasmids and integrons) and high-risk clones, facilitating rapid cross-border spread. Geographic disparities are striking: Asia accounts for 80% of MBL-producing Acinetobacter reports, while the Eastern Mediterranean and Africa show the highest prevalence of carbapenem-resistant A. baumannii (42.1% and 36.1%, respectively). In contrast, Europe and the Americas report prevalence below 1%, though absolute case numbers remain substantial due to robust surveillance. Phenotypic detection methods (combined disc test, E-test, and modified Hodge test) are practical in resource-limited settings but suffer from poor specificity and subjective interpretation. Genotypic methods (PCR, whole-genome sequencing, and MALDI-TOF MS) offer definitive gene identification but require specialized infrastructure and expertise. Critical risk factors for MBL acquisition include prior carbapenem exposure, prolonged ICU stays, invasive devices, immunosuppression, and healthcare-associated transmission. The absence of Food and Drug Administration (FDA)-approved MBL inhibitors forces reliance on antibiotics that have limited efficacy, high toxicity, and emerging resistance. Addressing this crisis demands a coordinated, multi-pronged strategy: strengthening global genomic surveillance; deploying rapid molecular diagnostics at the point of care; accelerating the development of novel MBL inhibitors; enforcing antimicrobial stewardship to curb carbapenem overuse; and implementing rigorous infection prevention and control measures.