The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant has proven to be highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here, we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Hamsters were inoculated with either SARS-CoV-2 Omicron or other SARS-CoV-2 variants. Animals were followed for weight loss, and upper and lower respiratory tract tissues were assessed for viral loads and histopathology. Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4%–10% weight loss by day 4 and 10%–17% weight loss by day 6. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection led to substantial viral replication in both the upper and lower respiratory tracts but demonstrated lower viral loads in lung parenchyma and reduced pulmonary pathology compared with WA1/2020 infection. These data suggest that the SARS-CoV-2 Omicron variant may result in robust upper respiratory tract infection, but less severe lower respiratory tract clinical disease, compared with prior SARS-CoV-2 variants. Funding for this study was provided by NIH grant CA260476, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute, and the Musk Foundation. Display omitted •Omicron-infected Syrian golden hamsters did not lose weight•Omicron-infected hamsters had lower viral loads in lung than other variants•Omicron-infected hamsters showed less severe lung pathology than other variants The SARS-CoV-2 Omicron variant has proven highly transmissible and has outcompeted the Delta variant in many regions of the world. In this study, investigators studied Omicron infection in Syrian golden hamsters. Although infection with prior SARS-CoV-2 variants led to substantial weight loss following infection in hamsters, infection with the Omicron variant did not result in any detectable weight loss, even at high challenge doses. Moreover, Omicron infection led to lower viral loads and reduced pathology in the lung compared with prior SARS-CoV-2 variants. These findings show that the SARS-CoV-2 Omicron variant led to less severe lower respiratory tract disease compared with prior SARS-CoV-2 variants in hamsters. Syrian golden hamsters infected with the SARS-CoV-2 Omicron variant did not lose weight and showed less virus in the lung and reduced lung pathology compared with hamsters infected with prior SARS-CoV-2 variants. These observations are consistent with emerging human data suggesting that Omicron infection is less severe than infection with prior variants.