BACKGROUND: Gay and bisexual men who have sex with men (MSM) in the rural United States are less likely to test for HIV and sexually transmitted infections (STIs) and use pre-exposure prophylaxis (PrEP) compared to urban MSM. Given the challenges in building brick-and-mortar facilities serving the sexual health needs of MSM in rural communities, there is a need to evaluate digital engagement strategies. Combine is a smartphone app designed to provide HIV prevention information and resources to MSM that may be particularly well suited to support rural MSM. HealthMindr, an app from which Combine is adapted, has previously been shown to increase HIV testing and PrEP uptake among urban MSM. Because rural MSM face additional barriers to accessing HIV prevention services, a motivational interview (MI) focused on HIV prevention strategies might enhance the effectiveness of Combine to increase uptake of HIV testing, STI testing, and PrEP. OBJECTIVE: This study aims to determine the effectiveness of the Combine app to increase HIV testing, STI testing, and PrEP initiation among rural cisgender MSM. We will also assess the effectiveness of 2 adjunctive interventions: the availability of free HIV and STI self-test kits and the offering of an MI. METHODS: In this type 2 hybrid effectiveness-implementation randomized controlled trial, we will assess the effectiveness of Combine to increase HIV testing, STI testing, and PrEP initiation among rural MSM across the Southern United States. A total of 464 men will be recruited and randomized to 1 of the 4 arms. Participants in all 4 arms will have access to most app features (eg, health resources, quizzes, health care provider locators, and ordering free condoms and lubricants). Using a 2×2 factorial design, half (232/464, 50%) of the participants will be randomized to receive access to free at-home HIV and STI self-test kits and half (232/464, 50%) will be randomized to receive an MI. Participants will complete surveys every 6 months to allow for assessment of self-reported outcomes: app use, HIV testing, STI testing, and PrEP initiation over the 24-month follow-up period. Self-reported PrEP uptake will be verified by dried blood spot testing or uploading a photograph of a PrEP prescription. RESULTS: Participant recruitment began in March 2024. As of July 2025, 395 participants have been enrolled and randomized. Recruitment is expected to be completed by December 2025. CONCLUSIONS: This trial will determine whether the Combine app increases HIV testing, STI testing, and PrEP uptake among rural MSM in the Southern United States. It will also provide critical information about the most effective strategies for implementing digital health interventions for rural MSM. TRIAL REGISTRATION: ClinicalTrials.gov NCT06205368; https://clinicaltrials.gov/study/NCT06205368. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/69540.