The prevalence of human papillomavirus (HPV) and its related cancers is a major global concern. In the United States, routine HPV vaccination is recommended for youth aged 11 or 12 years. Despite HPV being the most common sexually transmitted infection and the vaccine's proven efficacy, the vaccination rate among US youth remains below the recommended 80% completion rate. Mobile health (mHealth) interventions have demonstrated promise in improving health. Examining and synthesizing the current evidence about the impact of mHealth interventions on vaccination coverage in youth and intervention characteristics could guide future mHealth interventions aimed at mitigating the vaccination gap and disease burden. This study aims to conduct a systematic review to assess the effectiveness of mHealth interventions on parental intent to vaccinate youth against HPV and youth's vaccine uptake. We searched empirical papers through databases including Google Scholar, PubMed, CINAHL, PsycINFO, and Cochrane Library. The inclusion criteria were the following: (1) published between January 2011 and December 2022; (2) using mHealth aimed to improve HPV vaccination rate; (3) targeted unvaccinated youth or their parents; and (4) measured HPV-related knowledge, vaccination intention, or vaccine uptake. Overall, 3 researchers screened and appraised the quality of the eligible papers using the Melnyk Levels of Evidence and the Cochrane Grading of Recommendations Assessment, Development, and Evaluation methodology. Disagreements in search results and result interpretation were resolved through consensus. Overall, 17 studies that met the inclusion criteria were included in the final review. Most studies were conducted in the United States (14/17, 82%), used a randomized controlled trial design (12/17, 71%), and adopted behavior change theories or a culture-centric approach (10/17, 59%). mHealth interventions included SMS text message reminders, motivational SMS text messages, computer-tailored or tablet-tailored interventions, smartphoneapps, web-based tailored interventions, social media (Facebook) campaigns, digital videos, and digital storytelling interventions. Approximately 88% (15/17) of the mHealth interventions demonstrated positive effects on knowledge, intention, or behaviors related to HPV vaccination. Overall, 12% (2/17) reported limited or no intervention impact on vaccine uptake or vaccine series completion. Effective vaccine uptake was commonly seen in interventions based on behavior change theories and those that provided culturally relevant information. This systematic review identified the impact of mHealth interventions among unvaccinated youth and their parents, which showed improvement in HPV-related knowledge, vaccination intention, or vaccine initiation. The interventions that incorporated theories and culture-centric approaches revealed the most promising results. Although these outcomes are encouraging, future studies are needed to investigate factors associated with the success of interventions using SMS text messaging or social media. More studies are also needed for a better understanding of the intervention elements that boost the responses of age-specific and ethnicity-specific populations.