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Background: Social media public health campaigns have the advantage of tailored messaging at low cost and large reach, but little is known about what would determine their feasibility as tools for inducing attitude and behavior change. Objective: The aim of this study was to test the feasibility of designing, implementing, and evaluating a social media-enabled intervention for skin cancer prevention. Methods: A quasi-experimental feasibility study used social media (Twitter) to disseminate different message "frames" related to care in the sun and cancer prevention. Phase 1 utilized the Northern Ireland cancer charity's Twitter platform (May 1 to July 14, 2015). Following a 2-week "washout" period, Phase 2 commenced (August 1 to September 30, 2015) using a bespoke Twitter platform. Phase 2 also included a Thunderclap, whereby users allowed their social media accounts to automatically post a bespoke message on their behalf. Message frames were categorized into 5 broad categories: humor, shock or disgust, informative, personal stories, and opportunistic. Seed users with a notable following were contacted to be "influencers" in retweeting campaign content. A pre- and postintervention Web-based survey recorded skin cancer prevention knowledge and attitudes in Northern Ireland (population 1.8 million). Results: There were a total of 417,678 tweet impressions, 11,213 engagements, and 1211 retweets related to our campaign. Shocking messages generated the greatest impressions (shock, n=2369; informative, n=2258; humorous, n=1458; story, n=1680), whereas humorous messages generated greater engagement (humorous, n=148; shock, n=147; story, n=117; informative, n=100) and greater engagement rates compared with story tweets. Informative messages, resulted in the greatest number of shares (informative, n=17; humorous, n=10; shock, n=9; story, n=7). The study findings included improved knowledge of skin cancer severity in a pre- and postintervention Web-based survey, with greater awareness that skin cancer is the most common form of cancer (preintervention: 28.4% [95/335] vs postintervention: 39.3% [168/428] answered "True") and that melanoma is most serious (49.1% [165/336] vs 55.5% [238/429]). The results also show improved attitudes toward ultraviolet (UV) exposure and skin cancer with a reduction in agreement that respondents "like to tan" (60.5% [202/334] vs 55.6% [238/428]). Conclusions: Social media-disseminated public health messages reached more than 23% of the Northern Ireland population. A Web-based survey suggested that the campaign might have contributed to improved knowledge and attitudes toward skin cancer among the target population. Findings suggested that shocking and humorous messages generated greatest impressions and engagement, but information-based messages were likely to be shared most. The extent of behavioral change as a result of the campaign remains to be explored, however, the change of attitudes and knowledge is promising. Social media is an inexpensive, effective method for delivering public health messages. However, existing and traditional process evaluation methods may not be suitable for social media. [ABSTRACT FROM AUTHOR]