Background: In the United States, the most common sexually transmitted infection, human papillomavirus (HPV), causes genital warts and is associated with an estimated 33,700 newly diagnosed cancer cases annually. HPV vaccination, especially for preteens aged 11 to 12 years, is effective in preventing the acquisition of HPV and HPV-associated cancers. However, as of 2018, completion of the 2- or 3-dose HPV vaccination series increased only from 48.6% to 51.1% in teens aged 13 to 17 years, and this increase was observed only in boys. By comparison, 88.7% of teens had more than one dose of the recommended vaccine against tetanus, diphtheria, and acellular pertussis (Tdap), and 85.1% of teens had more than one dose of meningococcal vaccine. Immunizations for Tdap, meningococcal disease, and HPV can occur at the same clinical visit but often do not. Objective: Vaccination against HPV is recommended for routine use in those aged 11 to 12 years in the United States, yet it is underutilized. We aimed to develop an educational video game to engage preteens in the decision to vaccinate. Methods: Land of Secret Gardens is a metaphor for protecting seedlings (body) with a potion (vaccine). We screened 131 dyads of parents and preteens from 18 primary practices in North Carolina who had not initiated HPV vaccination. We measured vaccination intentions, story immersion, and game play and documented HPV vaccination rates. A total of 55 dyads were enrolled, and we randomly assigned 28 (21 completed) to play the game and 27 (26 completed) to the comparison group. Results: In total, 18 preteens reported playing the game. The vaccination self-efficacy score was higher in the comparison group than the intervention group (1.65 vs 1.45; P=.05). The overall mean decisional balance score trended toward greater support of vaccination, although differences between the groups were not significant.. Vaccine initiation and completion rates were higher in the intervention group (22% vs 15%; P=.31) than in the comparison group (9% vs 2%; P=.10), although the difference was not significant. Conclusions: Video games help preteens in the decision to pursue HPV vaccination. A serious video game on HPV vaccination is acceptable to parents and preteens and can be played as intended. Gamification is effective in increasing preteen interest in HPV vaccination, as game features support decision making for HPV vaccination.