Colistin (polymyxin E), a last-resort antibiotic for the treatment of multidrug-resistant Gram-negative bacterial infections, is becoming increasingly compromised by the rapid emergence and dissemination of resistance. The extensive use of colistin in agriculture and veterinary medicine has accelerated the spread of plasmid-mediated mobile colistin resistance (mcr) genes, facilitating transmission across human, animal, and environmental reservoirs. This review provides a comprehensive overview of the epidemiology, molecular mechanisms, and geographical distribution of colistin resistance in the Middle East and North Africa (MENA) region. Analysis of the available literature indicates that Tunisia reports the highest prevalence of colistin-resistant Gram-negative bacteria in North Africa (58.09%), followed by Egypt (24.76%), Algeria (14.29%), and Libya (2.86%). Across the region, mcr-1 is the predominant plasmid-mediated resistance determinant, whereas chromosomal alterations involving the mgrB, pmrA/pmrB, and phoP/phoQ regulatory systems are the principal non-plasmid-mediated mechanisms. Resistance has been documented in major clinical pathogens, including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, as well as in livestock, poultry, aquaculture, wildlife, food products, and environmental samples, highlighting the interconnected nature of resistance transmission under a One Health framework. The evidence demonstrates substantial geographical variability and significant gaps in surveillance across several MENA countries, limiting accurate regional burden estimates. Strengthening antimicrobial stewardship, harmonized surveillance programs, molecular monitoring of resistance determinants, and the implementation of One Health strategies are essential to limit the continued emergence and dissemination of colistin resistance throughout the region.