AbstractAntimicrobial resistance poses a significant public health challenge, particularly with the rise of gram‐negative hospital‐acquired infections resistant to carbapenems. Aztreonam–avibactam (ATM–AVI) is a promising new combination therapy designed to combat multidrug‐resistant (MDR) gram‐negative bacteria, including those producing metallo‐β‐lactamases (MBLs). Aztreonam, a monobactam antibiotic, is resistant to hydrolysis by MBLs but can be degraded by other β‐lactamases. Avibactam, a novel non‐β‐lactam β‐lactamase inhibitor, effectively neutralizes extended‐spectrum β‐lactamases (ESBLs) and AmpC β‐lactamases, restoring aztreonam's efficacy against resistant pathogens. This review covers the chemistry, mechanisms of action, spectrum of activity, pharmacokinetics, pharmacodynamics, and clinical efficacy of ATM–AVI. ATM–AVI combination has shown efficacy against a wide range of resistant Enterobacterales and other gram‐negative bacteria in both in vitro and clinical studies. Pharmacokinetic and pharmacodynamic analyses demonstrate that ATM–AVI maintains effective drug concentrations in the body, with dose adjustments recommended for patients with renal impairment. Clinical trials, including the REVISIT and ASSEMBLE studies, have demonstrated the safety and efficacy of ATM–AVI in treating complicated intra‐abdominal infections (cIAI), urinary tract infections (UTIs), and hospital‐acquired pneumonia (HAP) caused by MDR gram‐negative pathogens. The European Medicines Agency (EMA) has approved ATM–AVI for these indications, and further research is ongoing to optimize dosing regimens and expand its clinical use. This combination represents a critical advancement in the fight against antimicrobial resistance, offering a new therapeutic option for treating severe infections caused by MDR gram‐negative, including MBL‐producing, bacteria.