With the emergence of SARS-CoV-2, various non-pharmaceutical interventions were adopted to control virus transmission, including school closures. Subsequently, the introduction of vaccines mitigated not only disease severity but also the spread of SARS-CoV-2. This study leveraged an adapted SIR model and non-linear mixed-effects modeling to quantify the impact of remote learning, school holidays, the emergence of Variants of Concern (VOCs), and the role of vaccinations in controlling SARS-CoV-2 spread across 16 German federal states with an age-stratified approach. Findings highlight a significant inverse correlation (Spearman's ρ = −0.92, p < 0.001) between vaccination rates and peak incidence rates across all age groups. Model-parameter estimation using the observed number of cases stratified by federal state and age allowed to assess the effects of school closure and holidays, considering adjustments for vaccinations and spread of VOCs over time. Here, modeling revealed significant (p < 0.001) differences in the virus's spread among pre-school children (0–4), children (5–11), adolescents (12–17), adults (18–59), and the elderly (60+). The transition to remote learning emerged as a critical measure in significantly reducing infection rates among children and adolescents (p < 0.001), whereas an increased infection risk was noted among the elderly during these periods, suggesting a shift in infection networks due to altered caregiving roles. Conversely, during school holiday periods, infection rates among adolescents mirrored those observed when schools were open. Simulation exercises based on the model provided evidence that COVID-19 vaccinations might serve a dual purpose: they protect the vaccinated individuals and contribute to the broader community's safety.