BACKGROUND: Tobacco use disorder is a chronic, relapsing health condition that necessitates a chronic care approach. However, there are limited treatment strategies relevant to individuals who smoke across a continuum of motivation to quit. Further, there is no clear understanding of the mechanisms underlying treatment strategies to engage individuals who are not yet ready to quit smoking. METHODS: The current study will enroll 780 individuals who smoke and are unmotivated to quit within the next month through a nationwide remote clinical trial (NCT05513872). Participants are randomized to receive Practice Quitting or Motivational Interviewing counseling, with or without Nicotine Replacement Therapy product sampling. The primary outcome is incidence of an attempt to quit by 6 months post-treatment. The analytic strategy will examine treatment effects on quit attempts and smoking cessation, along with hypothesized treatment mediators to determine mechanisms of treatment outcomes. CONCLUSION: Individuals who are not yet ready to quit smoking are a critical group to target in population health management efforts for smoking cessation. We discuss key methodological considerations relevant to the design of future remote and mechanistic clinical trials for smoking cessation.