Background Vaccines are one of the most important achievements of modern medicine. However, their acceptance is only partial, with vaccine hesitancy and refusal representing a major health threat. Influenza vaccines have low compliance since repeated, annual vaccination is required. Influenza vaccines stimulate discussions both in the real world and online. Social media is currently a significant source of health and medical information. Elucidating the association between social media engagement and influenza vaccination is important and may be applicable to other vaccines, including ones against COVID-19. Objective The goal of this study is to characterize profiles of social media engagement regarding the influenza vaccine and their association with knowledge and compliance in order to support improvement of future web-associated vaccination campaigns. Methods A weblink to an online survey in Hebrew was disseminated over social media and messaging platforms. The survey answers were collected during April 2020. Anonymous and volunteer participants aged 21 years and over answered 30 questions related to sociodemographics; social media usage; influenza- and vaccine-related knowledge and behavior; health-related information searching, its reliability, and its influence; and COVID-19-related information searching. A univariate descriptive data analysis was performed, followed by multivariate analysis via building a decision tree to define the most important attributes associated with vaccination compliance. Results A total of 213 subjects responded to the survey, of whom 207 were included in the analysis; the majority of the respondents were female, were aged 21 to 40 years, had 1 to 2 children, lived in central Israel, were secular Israeli natives, had higher education, and had a salary close to the national average. Most respondents (128/207, 61.8%) were not vaccinated against influenza in 2019 and used social media. Participants that used social media were younger, secular, and living in high-density agglomerations and had lower influenza vaccination rates. The perceived influence and reliability of the information on social media about COVID-19 were generally similar to those perceptions about influenza. Conclusions Using social media is negatively linked to compliance with seasonal influenza vaccination in this study. A high proportion of noncompliant individuals can lead to increased consumption of health care services and can, therefore, overload these health services. This is particularly crucial with a concomitant outbreak, such as COVID-19. Health care professionals should use improved and targeted health communication campaigns with the aid of experts in social media. Targeted communication, based on sociodemographic factors and personalized social media usage, might increase influenza vaccination rates and compliance with other vaccines as well.