BACKGROUND Nondaily smoking is a widespread, increasingly prevalent pattern of smoking, particularly in ethnic minority and vulnerable populations. To date, no effective treatment approach for this type of smokers has been identified. OBJECTIVE This study aims to use a randomized controlled trial to evaluate proof-of-concept markers of the Smiling instead of Smoking (SiS) app, a smoking cessation smartphone app designed specifically for nondaily smokers. This app was developed iteratively and is now in its third version. Previous studies have demonstrated acceptability and feasibility when participants were onboarded in person (study 1) and remotely (study 2) and showed within-person changes in line with hypothesized mechanisms of change. This is the first randomized test of this app. METHODS In total, 225 adult nondaily smokers will be asked to undertake a quit attempt while using smoking cessation support materials for a period of 7 weeks. Participants will be randomized to use the SiS smartphone app, the National Cancer Institute smartphone app QuitGuide, or the National Cancer Institute smoking cessation brochure "Clearing the Air." Participants will take part in a 15-minute scripted onboarding phone call during which study staff will introduce participants to their support materials. Survey links will be sent 2, 6, 12, and 24 weeks after the participants' initially chosen quit date. The primary outcome is self-efficacy to remain abstinent from smoking at treatment end, measured using the Smoking Self-Efficacy Questionnaire. Secondary outcomes cover several domains relevant to treatment development and implementation: treatment acceptability (eg, satisfaction with smoking cessation support, measured using the Client Satisfaction Questionnaire, and app usability, measured using the System Usability Scale); treatment feasibility (eg, measured using the number of days participants used the SiS or QuitGuide app during the prescribed treatment period); and, in an exploratory way, treatment efficacy assessed using self-reported 30-day point prevalence abstinence. RESULTS Recruitment began in January 2021 and ended June 2022. The final 24-week follow-up was completed in January 2023. This trial is funded by the American Cancer Society. CONCLUSIONS This study is designed to test whether the prescribed use of the SiS app results in greater self-efficacy to abstain from smoking in nondaily smokers than commonly recommended alternative treatments and whether the SiS app treatment is acceptable and feasible. Positive results will mean that the SiS app warrants testing in a large-scale randomized controlled trial to test its effectiveness in supporting smoking cessation in nondaily smokers. The design of this study also provides insights into issues pertinent to smoking cessation smartphone app treatment development and implementation by measuring, in a randomized design, markers of treatment satisfaction, engagement with the technology and content of the treatment, and adherence to the treatment plan. BACKGROUND ClinicalTrials.gov NCT04672239; https://clinicaltrials.gov/ct2/show/NCT04672239. DERR1-10.2196/40867.