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When a new infectious outbreak emerges, governments must initially rely on non-pharmaceutical interventions (NPIs) to mitigate the impact of the pathogen. Although a strict stay-at-home requirement (i.e., lockdown) presents high effectiveness in reducing patients hospitalized in intensive care units (ICUs), it comes with unintended physical, psychological, and economic damages for the citizens. Using how Italy managed the COVID-19 outbreak from February to September 2020 on a national basis, this study aims at understanding the impact of implementation timing on the effectiveness of NPIs. Our findings may be helpful to avoid the implementation of stay-at-home requirements when it is not strictly necessary. A compartmental SEICRD model was developed to create the baseline scenario without NPIs. Generalized Poisson regressions were applied to study the change in effectiveness over-time of NPIs on Avoided ICUs for each one of the Italian regions. Our study suggests that although the stay-at-home requirement is the most effective measure in reducing ICU hospitalizations in regions encountering the outbreak early, its effectiveness decreases in regions encountering the outbreak later, where a set of other NPIs are more effective. We developed a reference of daily new cases when lockdown should be implemented or avoided, accordingly. Our findings could be useful to support policymakers in contrasting the pandemic and in limiting the societal and economic impact of stringent NPIs., (Copyright © 2022 Elsevier B.V. All rights reserved.)