Introduction COVID-19 was less severe in Sub-Saharan Africa (SSA) compared with Europe and North America. It is unclear whether these differences could be explained immunologically. Here we determined levels of ex vivo SARS-CoV-2 peptide-specific IFN-γ producing cells, and plasma cytokines and chemokines over the first month of COVID-19 diagnosis among Kenyan COVID-19 patients from urban and rural areas. Methods Between June 2020 and August 2022, we recruited and longitudinally monitored 188 COVID-19 patients from two regions in Kenya, Nairobi (urban, n = 152) and Kilifi (rural, n = 36), with varying disease severity – severe, mild/moderate, and asymptomatic. IFN-γ secreting cells were enumerated at 0-, 7-, 14- and 28-days post diagnosis by an ex vivo enzyme-linked immunospot (ELISpot) assay following in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with overlapping peptides from several SARS-CoV-2 proteins. A multiplexed binding assay was used to measure levels of 22 plasma cytokines and chemokines. Results Higher frequencies of IFN-γ-secreting cells against SARS-CoV-2 spike peptides were observed on the day of diagnosis among asymptomatic compared to patients with severe COVID-19. Higher concentrations of 17 of the 22 cytokines and chemokines measured were positively associated with severe disease, particularly interleukin (IL)-8, IL-18 and IL-1ra (p < 0.0001), while a lower concentration of SDF-1α was associated with severe disease (p < 0.0001). Concentrations of 8 and 16 cytokines and chemokines including IL-18 were higher among Nairobi asymptomatic and mild patients compared to their respective Kilifi counterparts. Conversely, concentrations for SDF-1α were higher in rural Kilifi compared to Nairobi (p = 0.012). Conclusion In Kenya, as seen elsewhere, pro-inflammatory cytokines and chemokines were associated with severe COVID-19, while an early IFN-γ cellular response to overlapping SARS-CoV-2 spike peptides was associated with reduced risk of disease. Living in urban Nairobi (compared with rural Kilifi) was associated with increased levels of pro-inflammatory cytokines and chemokines.