Gross Domestic Product (GDP) is commonly regarded as the best measure of a country's economic health. In 2020, China suffered from a relatively serious COVID-19 epidemic, which had a huge impact on economic development. This paper aims to accurately analyze the spatial and temporal variation pattern of the GDP contributed by the second and tertiary industries in Guangdong Province, China in the first quarter under the background of the epidemic. To this end, the remote sensing data of night-time light was taken as an indicator of GDP contributed by the secondary and tertiary industries (GDP 23). By combining the real-time monitoring data of the epidemic and point of interest (POI) data of Guangdong Province, the authors firstly determined that the epidemic was the factor that caused the decrease in urban total night light intensity (TNLI). Then they analyzed the fitting of various night light indices and different regression models to the GDP 23 of Guangdong Province. Based on this, the optimal index and model were selected for the spatial grid partition of GDP 23 and the comparison of GDP 23 with that in 2019. Afterward, the authors analyzed the impacts of COVID-19 on GDP 23 of Guangdong Province in the first quarter and the reasons from spatial-temporal perspectives according to the spatial simulation results of GDP 23. For the cities most affected by the epidemic, the most affected industries were obtained through the statistical analysis of POI data, aiming to scientifically guide the precise resumption of work and production in Guangdong Province. The results are as follows. The spatial distribution of GDP 23 in 2019 was highly consistent with that in 2020, and the heart of Guangdong's economic development consisted of Guangzhou, Shenzhen, Dongguan, and Foshan cities in the two years. In terms of temporal distribution, 21 cities in Guangdong Province were affected by COVID-19 at different degrees in 2020 compared to 2019. Among them, the cities with relatively developed economies were affected the most, including Shenzhen, Guangzhou, Dongguan, and Foshan. According to POI data and the spatial distribution difference of GDP 23 between 2019 and 2020, the cities having suffered the biggest economic impacts were Guangzhou and Zhongshan, where the leading industries included shopping, real estate, and enterprises and companies, while the cities with the highest increased amplitude of GDP 23 included Shaoguan and Shenzhen, where the leading industries consisted of finance, real estate, and shopping. Therefore, the provincial and municipal governments should formulate corresponding policies on the financial industry, life service industry, and shopping consumption in Guangzhou and Zhongshan cities, in order to accurately assist enterprises and companies to early resume work and production.