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While the effectiveness of lockdowns to reduce Coronavirus Disease-2019 (COVID-19) transmission is well established, uncertainties remain on the lifting principles of these restrictive interventions. World Health Organization recommends case positive rate of 5% or lower as a threshold for safe reopening. However, inadequate testing capacity limits the applicability of this recommendation, especially in the low-income and middle-income countries (LMICs). To develop a practical reopening strategy for LMICs, in this study, we first identify the optimal timing of safe reopening by exploring accessible epidemiological data of 24 countries during the initial COVID-19 surge. We find that a safe opening can occur two weeks after the crossover of daily infection and recovery rates while maintaining a negative trend in daily new cases. Epidemiologic SIRM model-based example simulation supports our findings. Finally, we develop an easily interpretable large-scale reopening (LSR) index, which is an evidence-based toolkit—to guide/inform reopening decision for LMICs.