Easy and effective vaccination methods could reduce mortality rates and morbidity due to vaccine-preventable influenza infections. In this study, we examined the use of microneedle patches to increase patient coverage through possible self-administration and enhance vaccine immunogenicity by targeted delivery to skin. We carried out a detailed study of protective immune responses after a single influenza vaccination to the skin of mice with a novel microneedle patch designed to facilitate simple and reliable vaccine delivery. Skin vaccination with inactivated virus-coated microneedles provided superior protection against lethal challenge compared to intramuscular injection as evidenced by effective virus clearance in lungs. Detailed immunologic analysis suggests that induction of virus neutralizing antibodies as well as enhanced anamnestic humoral and cellular responses contributed to improved protection by microneedle vaccination to the skin. These findings suggest that vaccination in the skin using a microneedle patch can improve protective immunity, and simplify delivery of influenza and possibly other vaccines.