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SARS-CoV-2 Omicron variant evolved into multiple sub-lineages, some showing increased transmissibility and immune evasion. Despite decreased risk of severe disease, paediatric hospitalization rose. However, factors influencing clinical outcomes remain unclear. A total of 458 whole-genome Omicron sequences from patients 0-17 years, diagnosed with SARS-CoV-2 at Bambino Gesù Children's Hospital (January-December 2023) were analysed. Clinical features, disease severity and circulating variants were assessed. Phylogenetic analysis was performed, and logistic regression identified factors associated with hospitalization. Among patients, 249 (54.4%) were male, with median age 0.6 years. Comorbidities were present in 105 (22.9%) patients, mainly immunocompromised (21.0%). Infections were predominantly from XBB (75.0%), JN.1 (12.4%), BA.5 (7.4%) and BA.2 (5.2%) clades. Upper respiratory infections predominated (73.8%), followed by asymptomatic (17.2%) and lower respiratory infections (4.6%), with nine patients having ≥ 1 co-infection. Comorbidities and lower respiratory infections were positively associated with hospitalization, while upper respiratory infections showed a negative association. Given the recent shift to RGN integrin-binding motif in Omicron sub-lineages, leading to altered pathogenesis, its presence was evaluated, revealing a predominance of RGN (N = 378, 84.6%). In conclusion, COVID-19 severity in paediatric patients was primarily driven by comorbidities and co-infections, while milder cases in healthy children may be associated with RGN integrin-binding motif.