<p>The rise of multidrug-resistant (MDR) bacteria is becoming a significant challenge, with colistin serving as the last-resort antibiotic for treating drug-resistant infections. The emergence of colistin-resistant (ColR) isolates has limited its clinical utility, highlighting the need for novel antimicrobial agents. Despite the recent approval of a few new antibiotics, there remains an urgent need for innovative strategies to address this critical issue. Developing and approving new antibiotics is a complex and time-consuming process, prompting researchers to investigate the use of colistin in combination with other compounds to treat ColR bacterial isolates. Non-antibiotic adjuvants, antimicrobial peptides, and nanotechnology-based strategies are among the most promising approaches used in combination with colistin. Natural compounds have shown promising results in numerous studies, aiding in the fight against antibiotic resistance. Furthermore, repurposing non-antibiotic medications in combination with colistin has demonstrated effectiveness and potential for enhancing colistin's efficacy. This review aimed to identify compounds effective against ColR isolates, with the hope that these approaches could offer solutions for combating these dangerous resistant strains in the near future.</p>