BACKGROUND: In response to the rapid global transmission of COVID-19, governments worldwide enacted lockdowns and other non-pharmaceutical interventions (NPI) to control the disease. In this study, we aim to quantify the influence of NPIs on the transmission of COVID-19 within selected European regions, specifically Spain (including the Basque Country) and Italy (including Tuscany), during the period of February to December 2020, which predates the initiation of COVID-19 vaccinations. We investigate potential correlations and associations between the implementation of NPIs, changes in COVID-19 transmission rates, and alterations in life expectancy across different age and sex categories from the year 2019 to 2020. METHODS: We use a Susceptible-Hospitalized-Asymptomatic/Mild-Recovered-Deceased (SHARD) ordinary differential equations model to analyze COVID-19 dynamics in the studied regions. The model calibration process was performed with empirical data on hospitalization and death to estimate the weekly transmission and death rates. To quantify reductions in life expectancy, we used established survival analysis techniques. RESULTS: The SHARD model effectively captures multiple waves of COVID-19, accurately representing peaks and aligning with the instantaneous reproduction number. Our analysis reveals a 66-78% reduction in transmission rates during the initial set of NPIs in March 2020, followed by a 34-55% reduction during the subsequent NPIs in October 2020. Additionally, the elderly and individuals with comorbidities experienced the most pronounced reductions in life expectancy. CONCLUSIONS: Our model calibration approach provides a valuable tool for evaluating the effectiveness of interventions across multiple waves of an epidemic. By applying this method to COVID-19 dynamics, we have demonstrated the capacity to quantify the impact of non-pharmaceutical interventions (NPIs) on transmission rates. These findings offer practical insights into the effectiveness of NPIs in mitigating COVID-19 spread and contribute to the broader understanding of epidemic control strategies.