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Introduction Cocaine use disorder (CUD) is a significant public health concern in the USA, with considerable prevalence and mortality and no Food and Drug Administration (FDA)-approved pharmacotherapies. Recent advances in addiction science emphasise the need for novel, mechanism-based treatments. Glucagon-like peptide-1 receptor agonists, such as semaglutide, have shown promise in modulating reward-related behaviours and may offer therapeutic benefits for CUD. We present a study protocol evaluating semaglutide, as an adjunct to cognitive behavioural therapy (CBT), as a novel approach for treating CUD.Methods and analysis This is a randomised, double-blind, placebo-controlled trial enrolling 75 treatment-seeking adults with CUD. Participants will be randomised 1:1 to receive either once-weekly semaglutide (0.25–1.0 mg) or placebo injections over 14 weeks, alongside weekly individual CBT. Primary outcomes include changes in neurophysiological reactivity to drug-related and non-drug-related motivationally relevant cues (late positive potential), behavioural economics (cocaine demand), craving (Cocaine Craving Questionnaire) and cocaine use (self-report, urine drug screens). Exploratory aims assess associations between mechanistic changes and cocaine use, consumption of other substances (ie, tobacco, alcohol and cannabis) and dose–response relationships. Data will be analysed using Bayesian statistical methods using an intention-to-treat approach.Ethics and dissemination The study has been approved by the UTHealth Committee for the Protection of Human Subjects (HSC-MS-25-0412) and is registered on ClinicalTrials.gov. All participants will provide written informed consent. Findings will be disseminated through peer-reviewed publications and scientific conferences.Trial registration number NCT07227948.