Resistance to commonly available antimicrobials is a major threat to the fight against endemic bacterial diseases in sub-Saharan Africa (SSA), with majority of the population unable to afford alternative effective antimicrobial options for management of these diseases. Diseases such as typhoid, cholera and invasive non-typhoidal salmonella (NTS) are among the key enteric infections endemic in most parts of SSA, especially in displaced populations and among the urban populations living in overcrowded informal settlements. Here, we explore the prevalence and the genomic epidemiology of these infections and the growing problem of multidrug resistance (MDR) including emerging resistance to the last line of treatment for these infections. Prevalence rates to commonly available antimicrobials including ampicillin, chloramphenicol, co-trimoxazole and tetracycline, now range between 65-80%, while 15-20% of recently studied isolates show reduced susceptibility to fluoroquinolones and emerging resistance to extended spectrum beta-lactams (ESBLs) mediated by the CTX-M-15 gene carried on a highly mobile genetic element. The high prevalence of MDR isolates including resistance to reserve antibiotics, calls for enhanced control and management options. It will be important for governments in the region to enhance the implementation of National Action Plans as guided by the Global Action Plan championed by the World Health Organisation (WHO) to combat the threat of antimicrobial resistance. However, these efforts will require a strong commitment and enhanced at all different levels of healthcare in order to yield meaningful results. In addition, utilization of WHO approved vaccines in the short-to-medium term and improvement of water and sanitation in the long term will reduce burden of disease and AMR in the region.