AbstractIndigenous peoples globally are at increased risk of COVID‐19‐associated morbidity and mortality. However, data that describe immune responses to SARS‐CoV‐2 infection in Indigenous populations are lacking. We evaluated immune responses in Australian First Nations peoples hospitalized with COVID‐19. Our work comprehensively mapped out inflammatory, humoral and adaptive immune responses following SARS‐CoV‐2 infection. Patients were recruited early following the lifting of strict public health measures in the Northern Territory, Australia, between November 2021 and May 2022. Australian First Nations peoples recovering from COVID‐19 showed increased levels of MCP‐1 and IL‐8 cytokines, IgG‐antibodies against Delta‐RBD and memory SARS‐CoV‐2‐specific T cell responses prior to hospital discharge in comparison with hospital admission, with resolution of hyperactivated HLA‐DR⁺CD38⁺ T cells. SARS‐CoV‐2 infection elicited coordinated ASC, Tfh and CD8⁺ T cell responses in concert with CD4⁺ T cell responses. Delta and Omicron RBD‐IgG, as well as Ancestral N‐IgG antibodies, strongly correlated with Ancestral RBD‐IgG antibodies and Spike‐specific memory B cells. We provide evidence of broad and robust immune responses following SARS‐CoV‐2 infection in Indigenous peoples, resembling those of non‐Indigenous COVID‐19 hospitalized patients.