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 safely reopening requires a two-week waiting period, after the crossover of daily infection and recovery rates – coupled with a post-crossover continuous negative trend in daily new cases. Epidemiologic SIRM model-based simulation analysis validates our findings. Finally, we develop an easily interpretable large-scale reopening (LSR) index, which is an evidence-based toolkit – to guide/inform the reopening decisions for LMICs.