Early postexposure immune responses to SARS-CoV-2 determine COVID-19 progression and severity. In humans, immune events are usually measured in blood or post-mortem by tissue sampling, and they do not fully reflect the early host response. By contrast, evaluation of mucosal immunity in humans soon after natural infection is difficult to achieve, which limits our understanding of early immune responses to infection. To circumvent such obstacles, we profiled early immune responses to different SARS-CoV-2 variants in K18-hACE2 transgenic mice, an animal model for COVID-19. Mice were intranasally infected with ancestral SARS-CoV-2 (D614G), Beta or Delta virus and monitored for viral loads, clinical symptoms and immune responses in the lungs and spleen over time using a panel of high-throughput assays. The challenge infection led to a divergence in lung viral loads, inflammation and immune cell accumulation between tested viruses. Beta viral loads were rapidly increased in the lungs and induced high abundances of cytokines and chemokines and increased pulmonary influx of monocytes and macrophages. Spleen-residing CD4+ T cells selectively increased the expression of differentiation and activation markers during the first week post-challenge. Lung CD4+ and CD8+ T cells upregulated activation, differentiation or homing markers (e.g. CXCR3, CD103, CD69 and CD44) starting one-week post-infection. Virus-neutralizing antibodies and S-peptide-specific T cell responses developed irrespective of the virus variant and were detected earliest 7 days post-infection (DPI). Virus-specific immune responses augmented towards 10 DPI and were accompanied by reduced lung viral loads and prolonged survival of the mice. Our data show early immune responses to distinct SARS-CoV-2 variants, enrich knowledge about COVID-19 pathogenesis and could contribute to developing pan-variant countermeasures by informing about the variability of immune responses modulated via variant-specific mutations.