The unprecedented amount and sources of information during the COVID-19 pandemic resulted in an indiscriminate level of misinformation that was confusing and compromised healthcare access and delivery. The World Health Organization (WHO) called this an ‘infodemic’, and conspiracy theories and fake news about COVID-19, plagued public health efforts to contain the COVID-19 pandemic. National and international public health priorities expanded to counter misinformation. As a multi-disciplinary study encompassing expertise from public health, informatics, and communication, this research focused on eliciting strategies to better understand and combat misinformation on COVID-19. The study hypotheses is that 1) factors influencing vaccine-acceptance like socio-demographic factors, COVID-19 knowledge, trust in institutions, and media related factors could be leveraged for public health education and intervention; and 2) individuals with a high level of knowledge regarding COVID-19 prevention and control have unique behaviors and practices, like nuanced media literacy and validation skills that could be promoted to improve vaccine acceptance and preventative health behaviors. In this biphasic study an initial survey of 1,498 individuals sampled from Amazon Mechanical Turk (MTurk) assessed socio-demographic factors, an 18-item test of COVID-19 knowledge, trust in healthcare stakeholders, and measures of media literacy and consumption. Subsequently, using the Positive Deviance Framework, a diverse subset of 25 individuals with high COVID-19 knowledge scores were interviewed to identify these deviants’ information and media practices that helped avoid COVID-19 misinformation. Access to primary care, higher educational attainment and living in urban communities were positive socio-demographic predictors of COVID-19 vaccine acceptance emphasizing the need to invest in education and rural health. High COVID-19 knowledge and trust in government and health providers were also critical factors and associated with a higher level of trust in science and credible information sources like the Centers for Disease Control (CDC) and health experts. Positive deviants practiced media literacy skills that emphasized checking sources for scientific basis as well as hidden bias; cross-checking information across multiple sources and verifying health information with scientific experts. These identified information validation and confirmation practices may be useful in educating the public and designing strategies to better protect communities against harmful health misinformation.