Abstract: With the increasing impact of climate change on public health, there is an urgent need to evaluate the detrimental effect of non-optimal ambient temperature on health and quantify the temperature-related mortality and corresponding economic losses. Based on the national database of weather conditions and mortality records in 272 main cities in China from 1 January 2013 to 31 December 2015, time-series analyses are conducted to estimate the exposure-response association between temperature and mortality. Besides, meteorological, socioeconomic, and demographic data for cities across China are collected to quantify the attributable deaths and corresponding economic losses due to low and high temperatures in 31 provinces, autonomous regions and municipalities of China. The exposure-response curve for the association between ambient temperature and mortality is J-shaped, with increased mortality risks for both low and high temperatures. As estimated, 842.4 (95%CI: 659.3—1022.0) thousand and 235.8 (95%CI: 146.9—321.7) thousand deaths are attributable to low and high temperatures in 2020 in China, respectively. The corresponding economic losses are 1701.11 (95%CI: 1335.35—2059.77) billion and 509.74 (95%CI: 317.97—694.59) billion Chinese yuan, respectively. The proportion of the overall economic loss to the gross domestic product (GDP) is 2.18%. Non-optimal ambient temperature exposure has led to substantial mortality and economic loss in China. It is necessary to strengthen actions to deal with the health threats of climate change and non-optimal ambient temperature, and local adaptation measures should be taken to protect public health in the future.