Natural and non-natural factors have combined effects on the trajectory of COVID-19 pandemic, but it is difficult to make them separate. To address this problem, a two-stepped methodology is proposed. First, a compound natural factor (CNF) model is developed via assigning weight to each of seven investigated natural factors, i.e., temperature, humidity, visibility, wind speed, barometric pressure, aerosol and vegetation in order to show their coupling relationship with the COVID-19 trajectory. Onward, the empirical distribution based framework (EDBF) is employed to iteratively optimize the coupling relationship between trajectory and CNF to express the real interaction. In addition, the collected data is considered from the backdate, i.e., about 23 days—which contains 14-days incubation period and 9-days invalid human response time—due to the non-availability of prior information about the natural spreading of virus without any human intervention(s), and also lag effects of the weather change and social interventions on the observed trajectory due to the COVID-19 incubation period; Second, the optimized CNF-plus-polynomial model is used to predict the future trajectory of COVID-19.Results revealed that aerosol and visibility show the higher contribution to transmission, wind speed to death, and humidity followed by barometric pressure dominate the recovery rates, respectively. Consequently, the average effect of environmental change to COVID-19 trajectory in China is minor in all variables, i.e., about -0.3%, +0.3% and +0.1%, respectively. In this research, the response analysis of COVID-19 trajectory to the compound natural interactions presents a new prospect on the part of global pandemic trajectory to environmental changes.