Invasive non-typhoidal Salmonella (iNTS) disease continues to be a significant public health problem in sub-Saharan Africa. Common clinical misdiagnosis, antimicrobial resistance, high case fatality and lack of a vaccine make iNTS a priority for global health research. Using whole genome sequence analysis of 164 invasive Salmonella isolates obtained through population-based surveillance between 2008 and 2016, we conducted genomic analysis of the serovars causing invasive Salmonella diseases in rural Gambia. The incidence of iNTS varied over time. The proportion of atypical serovars causing disease increased over time from 40 to 65 % compared to the typical serovars Enteritidis and Typhimurium that decreased from 30 to 12 %. Overall iNTS case fatality was 10%, but case fatality associated with atypical iNTS alone was 10 %. Genetic virulence factors were identified in 14/70 (20 %) typical serovars and 45/68 (66 %) of the atypical serovars and were associated with: invasion, proliferation and/or translocation (Clade A); and host colonization and immune modulation (Clade G). Among Enteritidis isolates, 33/40 were resistant to four or more of the antimicrobials tested, except ciprofloxacin, to which all isolates were susceptible. Resistance was low in Typhimurium isolates, but all 16 isolates were resistant to gentamicin. The increase in incidence and proportion of iNTS disease caused by atypical serovars is concerning. The increased proportion of atypical serovars and the high associated case fatality may be related to acquisition of specific genetic virulence factors. These factors may provide a selective advantage to the atypical serovars. Investigations should be conducted elsewhere in Africa to identify potential changes in the distribution of iNTS serovars and the extent of these virulence elements.