Background: South Africa reported a notable increase in COVID-19 cases from mid-November, 2021, onwards, starting in Tshwane District, which coincided with the rapid community spread of the SARS-CoV-2 omicron (B.1.1.529) variant. This increased infection rate coincided with a rapid increase in paediatric COVID-19-associated admissions to hospital (hereafter referred to as hospitalisations). Methods: The Tshwane Maternal-Child COVID-19 study is a multicentre observational study in which we investigated the clinical manifestations and outcomes of paediatric patients (aged ≤19 years) who had tested positive for SARS-CoV-2 and were admitted to hospital for any reason in Tshwane District during a 6-week period at the beginning of the fourth wave of the COVID-19 epidemic in South Africa. We used five data sources, which were: (1) COVID-19 line lists; (2) collated SARS-CoV-2 testing data; (3) SARS-CoV-2 genomic sequencing data; (4) COVID-19 hospitalisation surveillance; and (5) clinical data of public sector COVID-19-associated hospitalisations among children aged 13 years and younger. Findings: Between Oct 31 and Dec 11, 2021, 6287 children and adolescents in Tshwane District were recorded as having COVID-19. During this period, 2550 people with COVID-19 were hospitalised, of whom 462 (18%) were aged 19 years or younger. The number of paediatric cases was higher than in the three previous SARS-CoV-2 waves, uncharacteristically increasing ahead of adult hospitalisations. 75 viral samples from adults and children in the district were sequenced, of which 74 (99%) were of the omicron variant. Detailed clinical notes were available for 138 (75%) of 183 children aged ≤13 years with COVID-19 who were hospitalised. 87 (63%) of 138 children were aged 0–4 years. In 61 (44%) of 138 cases COVID-19 was the primary diagnosis, among whom symptoms included fever (37 [61%] of 61), cough (35 [57%]), shortness of breath (19 [31%]), seizures (19 [31%]), vomiting (16 [26%]), and diarrhoea (15 [25%]). Median length of hospital stay was 2 days [IQR 1–3]). 122 (88%) of 138 children with available data needed standard ward care and 27 (20%) needed oxygen therapy. Seven (5%) of 138 children were ventilated and four (3%) died during the study period, all related to complex underlying copathologies. All children and 77 (92%) of 84 parents or guardians with available data were unvaccinated to COVID-19. Interpretation: Rapid increases in paediatric COVID-19 cases and hospitalisations mirror high community transmission of the SARS-CoV-2 omicron variant in Tshwane District, South Africa. Continued monitoring is needed to understand the long-term effect of the omicron variant on children and adolescents. Funding: South African Medical Research Council, South African Department of Science & Innovation, G7 Global Health Fund.