Salmonella is the leading cause of typhoidal and non-typhoidal infections in the world. The entry of Salmonella into the bloodstream causes an invasive disease state, resulting to high morbidity and mortality rates, especially in children. Owing to the misuse of antibiotics, certain Salmonella serovars are multi-drug resistant and do not respond to traditional antibiotics, such as ampicillin and trimethoprim-sulphamethoxazole, presenting a significant challenge for healthcare practitioners in treating and controlling the spread of this disease. Therefore, expensive third-generation cephalosporins, such as ceftriaxone, are currently used to treat Salmonella infection. However, a novel serovar of Salmonella that resists ceftriaxone was recently identified in Saudi Arabia, indicating wide spread Salmonella resistance. A comprehensive literature review on ceftriaxone resistance in Salmonella is therefore necessary to reflect upon current challenges. In this report, we provide a summary of Salmonella incidence, mechanisms of ceftriaxone resistance in Salmonella, and current treatment options.