Background: Despite the overwhelming benefits of vaccinations, suboptimal public confidence in vaccines keeps immunization rates in the U.S far from ideal levels. Purpose: To assess the efficacy of a high school video set curriculum, on vaccine history, science, and safety, in improving vaccine knowledge. Methods: Sample included high school students in Virginia, who had completed required biology coursework. After being assigned to either the control or experimental group, their knowledge on vaccines was assessed before and after viewing the curriculum videos. Results: Experimental group students showed greater knowledge increases after viewing the videos. Examined by individual question, twelve out of eighteen questions in the experimental group had significant improvement in accuracy/knowledge, compared to one out of eighteen among the controls. Discussion: Our study demonstrates the value of using videos to convey vaccine-related knowledge to high schoolers. This knowledge can favorably impact rates of acute infectious disease as well as chronic conditions such as polio, cervical cancer, and long COVID syndrome. Translation to Health Education Practice: Such educational videos may be integrated into the state curricula so high school students can understand the impact, safety, and efficacy of vaccines and make informed public health decisions as adults.