BackgroundThe Coronavirus Disease (COVID-19) caused by SARS-CoV-2 infections remains a significant health challenge worldwide. There is paucity of evidence on the influence of the universal health coverage (UHC) and global health security (GHS) nexus on SARS-CoV-2 infection risk and outcomes. This study aimed to investigate the effects of UHC and GHS nexus and interplay on SARS-CoV-2 infection rate and case-fatality rates (CFR) in Africa.MethodsThe study employed descriptive methods to analyze the data drawn from multiple sources as well used structural equation modeling (SEM) with maximum likelihood estimation to model and assess the relationships between independent and dependent variables by performing path analysis.ResultsIn Africa, 100% and 18% of the effects of GHS on SARS-CoV-2 infection and RT-PCR CFR, respectively were direct. Increased SARS-CoV-2 CFR was associated with median age of the national population (β = -0.1244, [95% CI: -0.24, -0.01],P= 0.031 ); COVID-19 infection rate (β = -0.370, [95% CI: -0.66, -0.08],P= 0.012 ); and prevalence of obesity among adults aged 18 + years (β = 0.128, [95% CI: 0.06,0.20],P= 0.0001) were statistically significant. SARS-CoV-2 infection rates were strongly linked to median age of the national population (β = 0.118, [95% CI: 0.02,0.22 ],P= 0.024); population density per square kilometer, (β = -0.003, [95% CI: -0.0058, -0.00059],P= 0.016 ) and UHC for service coverage index (β = 0.089, [95% CI: 0.04,0.14,P= 0.001 ) in which their relationship was statistically significant.ConclusionsThe study shade a light that UHC for service coverage, and median age of the national population, population density have significant effect on COVID-19 infection rate while COVID-19 infection rate, median age of the national population and prevalence of obesity among adults aged 18 + years were associated with COVID-19 case-fatality rate. Both, UHC and GHS do not emerge to protect against COVID-19-related case fatality rate.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12992-023-00949-2.