Background The COVID-19 pandemic has necessitated a rapid shift in how individuals interact with and receive fundamental services, including health care. Although telemedicine is not a novel technology, previous studies have offered mixed opinions surrounding its utilization. However, there exists a dearth of research on how these opinions have evolved over the course of the current pandemic. Objective This study aims to evaluate how the language and sentiment surrounding telemedicine has evolved throughout the COVID-19 pandemic. Methods Tweets published between January 1, 2020, and April 24, 2021, containing at least one telemedicine-related and one COVID-19–related search term (“telemedicine-COVID”) were collected from the Twitter full archive search (N=351,718). A comparator sample containing only COVID-19 terms (“general-COVID”) was collected and sampled based on the daily distribution of telemedicine-COVID tweets. In addition to analyses of retweets and favorites, sentiment analysis was performed on both data sets in aggregate and within a subset of tweets receiving the top 100 most and least retweets. Results Telemedicine gained prominence during the early stages of the pandemic (ie, March through May 2020) before leveling off and reaching a steady state from June 2020 onward. Telemedicine-COVID tweets had a 21% lower average number of retweets than general-COVID tweets (incidence rate ratio 0.79, 95% CI 0.63-0.99; P=.04), but there was no difference in favorites. A majority of telemedicine-COVID tweets (180,295/351,718, 51.3%) were characterized as “positive,” compared to only 38.5% (135,434/351,401) of general-COVID tweets (P<.001). This trend was also true on a monthly level from March 2020 through April 2021. The most retweeted posts in both telemedicine-COVID and general-COVID data sets were authored by journalists and politicians. Whereas the majority of the most retweeted posts within the telemedicine-COVID data set were positive (55/101, 54.5%), a plurality of the most retweeted posts within the general-COVID data set were negative (44/89, 49.4%; P=.01). Conclusions During the COVID-19 pandemic, opinions surrounding telemedicine evolved to become more positive, especially when compared to the larger pool of COVID-19–related tweets. Decision makers should capitalize on these shifting public opinions to invest in telemedicine infrastructure and ensure its accessibility and success in a postpandemic world.