The reluctance of people to receive safe and recommended available vaccines is a well-documented public health challenge. As information and communication technologies evolve, this challenge gets more complex and even harder to manage during complex public health situations. In this experimental study, we examine the relationship between vaccine information frames (with scientific information vs. without scientific information) and channels (through government vs. religious organizations) and vaccination willingness in the U.S. in the context of a pandemic. Additionally, we evaluate the interaction between vaccine skepticism, vaccine information frames, and vaccine information channels on vaccination willingness. This experimental study uses data from Amazon Mechanical Turk (MTURK) to evaluate the relationships between vaccine skepticism, vaccine information frames, and channels on vaccination willingness. We find that contrary to our hypothesis, a vaccine advisory framed with scientific information decreases people’s vaccination willingness compared to one framed without scientific information. Additionally, the impact of framing on vaccination willingness is conditioned on participants’ skepticism—participants who hold skepticism toward the vaccine but received information framed with scientific information score significantly higher in vaccination willingness compared to participants who do not hold skepticism toward a vaccine. The results suggest that the factors impacting vaccination willingness are complex and nuanced. Thus, policymakers should be more strategic with the delivery of vaccination information, especially during complex health crises.