Shigellosis is an infectious diarrheal disease caused by Shigella from the family Enterobacteriaceae. Shigella is composed of four species and serogroups capable of causing shigellosis; their distribution, pathogenesis, and antibiotic susceptibility patterns differ. It is transmitted via direct and indirect contact such as the faecal-oral route and sexually among men who have sex with men (MSM). Although it is more prevalent and fatal in children and immunocompromised individuals in developing areas, the infection can occur in people in all age groups in developed and low-income countries. The disease can be self-limiting or severe in some cases. Beta-lactams, fluoroquinolones, macrolides, sulfonamides, and tetracycline are among the common antibiotics used for the pharmaceutical therapy of severe shigellosis to prevent fatal consequences. The broad range of Shigella serotypes and unrestrictive use of antibiotics in public health and agriculture has induced the prevalence of antibiotic-resistant species. It has stalled the treatment of the disease. The development and global distribution of multidrug-resistant Shigella seriously threaten public health. The evolution of several genes conferring resistance to the different antibiotic classes employed in the treatment of shigellosis has been documented in many countries. These genes may be chromosomal or plasmid-borne, and their acquisition or transmission is aided by horizontal gene transfer. The resistant genes encode several biochemical mechanisms of antibiotic resistance (AR) such as efflux pumps and alteration of drugs, among others. Genomics surveillance of resistant Shigella is crucial in the early and efficient detection of resistant genes, which will guide the implementation of novel interventions such as the design of effective antibiotics to combat antibiotic resistance and fatalities of shigellosis.