Background: The COVID-19 pandemic led to unprecedented mitigation efforts that disrupted the daily lives of millions. Beyond the general health repercussions of the pandemic itself, these measures also present a challenge to the world’s mental health and health care systems. Considering that traditional survey methods are time-consuming and expensive, we need timely and proactive data sources to respond to the rapidly evolving effects of health policy on our population’s mental health. Many people in the United States now use social media platforms such as Twitter to express the most minute details of their daily lives and social relations. This behavior is expected to increase during the COVID-19 pandemic, rendering social media data a rich field to understand personal well-being. Objective: This study aims to answer three research questions: (1) What themes emerge from a corpus of US tweets about COVID-19? (2) To what extent did social media use increase during the onset of the COVID-19 pandemic? and (3) Does sentiment change in response to the COVID-19 pandemic? Methods: We analyzed 86,581,237 public domain English language US tweets collected from an open-access public repository in three steps. First, we characterized the evolution of hashtags over time using latent Dirichlet allocation (LDA) topic modeling. Second, we increased the granularity of this analysis by downloading Twitter timelines of a large cohort of individuals (n=354,738) in 20 major US cities to assess changes in social media use. Finally, using this timeline data, we examined collective shifts in public mood in relation to evolving pandemic news cycles by analyzing the average daily sentiment of all timeline tweets with the Valence Aware Dictionary and Sentiment Reasoner (VADER) tool. Results: LDA topics generated in the early months of the data set corresponded to major COVID-19–specific events. However, as state and municipal governments began issuing stay-at-home orders, latent themes shifted toward US-related lifestyle changes rather than global pandemic-related events. Social media volume also increased significantly, peaking during stay-at-home mandates. Finally, VADER sentiment analysis scores of user timelines were initially high and stable but decreased significantly, and continuously, by late March. Conclusions: Our findings underscore the negative effects of the pandemic on overall population sentiment. Increased use rates suggest that, for some, social media may be a coping mechanism to combat feelings of isolation related to long-term social distancing. However, in light of the documented negative effect of heavy social media use on mental health, social media may further exacerbate negative feelings in the long-term for many individuals. Thus, considering the overburdened US mental health care structure, these findings have important implications for ongoing mitigation efforts.