BACKGROUND: Health promotion and education programs are increasingly being adapted and developed for delivery through digital technologies. With this shift toward digital health approaches, it is important to identify design strategies in health education and promotion programs that enhance participant engagement and promote behavior change. OBJECTIVE: This study aimed to examine the impact of an experiment testing various mobile health (mHealth) skin cancer prevention messages on sun protection intentions and message perceptions among American college students. METHODS: A sample of 134 college students aged 18 years or older participated in a 2×2×2 between-subjects experimental study, designed to examine the individual and combinatory effects of multiple dimensions (human presence, screen size, and interactivity) of digital technologies. The primary study outcome was intention to use sun protection; secondary outcomes included attitudes toward the information, two dimensions of trust, and information processing. RESULTS: Generally, intention to use sun protection was positively associated with the presence of human characters in the health educational messages (P<.001), delivering educational health messages on a large screen (ie, iPad; P<.001), and higher interactivity (P<.001). Only human presence produced more favorable attitudes (P=.02). Affective trust was positively associated with human presence (P=.006) and large screen size (P<.001), whereas cognitive trust was positively associated with human presence (P<.001) and small screen size (P=.007). Moreover, large screen size led to more heuristic processing (P=.03), whereas small screen size led to more systematic processing (P=.04). CONCLUSIONS: This experimental study demonstrates that the impact of mHealth skin cancer prevention messages differs based on platform and delivery design features. Effects on behavioral intentions, attitudes, and trust were found for conditions with human presence, highlighting the importance of including this feature in mHealth programs. Results from this experimental study can be used to optimize the design of mHealth educational interventions that promote sun protection.