Carbapenem-resistant Gram-negative bacteria (CR-GNB) have experienced an alarming surge in prevalence in recent years, escalating into a critical global healthcare crisis. As carbapenems represent the last line of defense against such pathogens, infections caused by CR-GNB have become increasingly challenging to treat, given the restricted therapeutic options and heightened mortality risks. The discovery and development of alternative therapeutic strategies that present novel avenues against multi-drug-resistant organisms are gaining increased attention, presenting a pressing need for innovative solutions. Our comprehensive review delves into the multifaceted landscape of carbapenem resistance in Gram-negative bacteria in response to this urgent challenge. The scope of this review aims to provide an up-to-date and in-depth exploration regarding the mode of action of carbapenem and the resisting mechanisms of carbapenem in GNB. Additionally, it discusses the state of the art of some clinical therapies for the treatment of infections caused by CR-GNB. Moreover, it describes several combinational and alternative therapies to combat CR-GNB, including the computational approach of "molecular docking". In light of the conclusions of this review, we call for the implementation of these strategies to develop comprehensive approaches to mitigate carbapenem resistance in Gram-negative bacteria.