Antimicrobial resistance (AMR) is a global health challenge, significantly impacting the treatment of infectious diseases. Salmonella enterica, a zoonotic pathogen, is a major cause of gastroenteritis and contributes significantly to morbidity and mortality in Africa. This study aimed to investigate the distribution of antimicrobial resistance genes (ARGs) in S. enterica isolates from food and human sources across four African countries (Zanzibar, Morocco, Nigeria, and Ghana) using bioinformatics approaches. Isolates were collected from hospitalized patients in Zanzibar, meat from animal-derived foods in Morocco, stool samples in Nigeria, and human salmonellosis cases in Ghana. Whole genome sequencing (WGS) data were analyzed using ABRIcate and the CARD database to identify ARGs. Data visualization, including bar charts and network graphs, was performed to illustrate gene prevalence and coresistance patterns. A total of 38 distinct ARGs were identified across all isolates, with significant regional differences. Beta-lactams were the most prevalent class of resistance genes, particularly penams and cephalosporins. In Ghana, penam resistance genes were the most common, followed by cephalosporins and fluoroquinolones. Moroccan isolates showed high resistance to penams, cephalosporins, and cephamycins. Nigerian isolates exhibited significant resistance to fluoroquinolones, cephalosporins, and penams. Zanzibar isolates were dominated by fluoroquinolone resistance genes, with moderate occurrences of penam and aminoglycoside resistance genes. Network analysis revealed tolC, acrB, and marA as central nodes, highlighting their critical role in multidrug resistance profiles. This study highlights the extensive diversity and dominance of beta-lactam resistance genes in S. enterica isolates across four African countries. The findings emphasize the need for enhanced genomic surveillance, prudent antibiotic use, and targeted interventions to mitigate AMR and its public health impact.