Social media human papillomavirus (HPV) vaccination interventions show promise for increasing HPV vaccination rates. An important consideration for the implementation of effective interventions into real-world practice is the translation potential, or external validity, of the intervention. To this end, we conducted a systematic literature review to describe the current body of evidence regarding the external validity of social media HPV vaccination-related interventions. Constructs related to external validity were based on the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework. Seventeen articles published between 2006 and 2020 met the inclusion criteria. Three researchers independently coded each article using a validated RE-AIM framework. Discrepant codes were discussed with a fourth reviewer to gain consensus. Of these 17 studies, 3 were pilot efficacy studies, 10 were randomized controlled trials (RCTs) to evaluate effectiveness, 1 was a population-based study, and 3 did not explicitly state which type of study was conducted. Reflecting this distribution of study types, across all studies the mean level of reporting RE-AIM dimensions varied with reach recording 90.8%, effectiveness (72.1%), adoption (40.3%), implementation (45.6%), and maintenance (26.5%). This review suggests that while the current HPV vaccination social media-driven interventions provide sufficient information on internal validity (reach and effectiveness), few have aimed to gather data on external validity needed to translate the interventions into real world implementation. Our data suggest that implementation research is needed to move HPV vaccination-related interventions into practice. Included in this review are recommendations for enhancing the design and reporting of these HPV vaccination social media-related interventions.