When a major, sudden infectious disease occurs, people tend to react emotionally and display reactions such as tension, anxiety, fear, depression, and somatization symptoms. Social media played a substantial awareness role in developing countries during the outbreak of coronavirus disease 2019 (COVID-19). This study aimed to analyze public opinion regarding COVID-19 and to explore the trajectory of psychological status and online public reactions to the COVID-19 pandemic by examining online content from Weibo in China. This study consisted of three steps: first, Weibo posts created during the pandemic were collected and preprocessed on a large scale; second, public sentiment orientation was classified as “optimistic/pessimistic/neutral” orientation via natural language processing and manual determination procedures; and third, qualitative and quantitative analyses were conducted to reveal the trajectory of public psychological status and online public reactions during the COVID-19 pandemic. Public psychological status differed in different periods of the pandemic (from December 2019 to May 2020). The newly confirmed cases had an almost 1-month lagged effect on public psychological status. Among the 15 events with high impact indexes or related to government decisions, there were 10 optimism orientation > pessimism orientation (OP) events (2/3) and 5 pessimism orientation > optimism orientation (PO) events (1/3). Among the top two OP events, the high-frequency words were “race against time” and “support,” while in the top two PO events, the high-frequency words were “irrationally purchase” and “pass away.” We proposed a hypothesis that people developed negative self-perception when they received PO events, but their cognition was developed by how these external stimuli were processed and evaluated. These results offer implications for public health policymakers on understanding public psychological status from social media. This study demonstrates the benefits of promoting psychological healthcare and hygiene activity in the early period and improving risk perception for the public based on public opinion and the coping abilities of people. Health managers should focus on disseminating socially oriented strategies to improve the policy literacy of Internet users, thereby facilitating the disease prevention work for the COVID-19 pandemic and other major public events.