This retrospective study aimed to investigate the impact of the emergence of new variants and the epidemiological scenario on hospitalization rates of unvaccinated children (0-12 years) in Brazil. The study included 1,614 children admitted to a hospital between March 2020 and December 2022, with only 101 (6.3%) of them testing positive for COVID-19 via RT-PCR. The frequency of COVID-19 cases increased from 7.5% in 2020 to 9.3% in 2022 with the emergence of the Omicron variant. Children over five years old with comorbidities accounted for the majority of cases (69% [70/101]). Sickle cell anemia was the most frequent comorbidity (20%), and flu disease (36% [36/101]) and decompensation of underlying disease (33% [33/101]) were the main reasons for hospitalization. Co-infection was detected in 11% of cases, with RSV being the most common viral pathogen (71%). Hospital readmission occurred in 26% of cases, with a higher frequency in children over five years old. The death rate was 2.2%, with comorbidities such as cystic fibrosis and congenital heart disease as risk factors. These findings emphasize the need to prioritize vaccination with monovalent Omicron XBB for high-risk groups, including children over five years old with comorbidities, to mitigate the impact of new variants and reduce severe disease outcomes.