question: INTRODUCTION The prevalence of tobacco smoking in pregnancy remains elevated in some disadvantaged populations of women. One group is those who use alcohol and/or other psychoactive substances during pregnancy, with tobacco use prevalence estimates ranging from 71% to 95%. Although effective evidence-based cessation treatments exist, few women with co-occurring substance use problems successfully stop smoking during pregnancy. There is limited information about treatments that specifically target this group and a summary of the available research is required to assist and enhance the development of innovative cessation interventions. This article describes a protocol for a comprehensive review of studies that have trialled behavioural and/or pharmacological tobacco cessation interventions in populations of pregnant women who are nicotine dependent and use alcohol and/or other psychoactive substances. METHODS AND ANALYSIS The review will undertake literature searches in MEDLINE, PsycINFO, CINAHL, EMBASE and ProQuest databases, as well as the grey literature. Studies of any design methodology will be included if they describe changes to tobacco smoking behaviours in quantitative terms. No restriction on year of publication or published language will apply. Participants include pregnant women of any age, who smoke tobacco, who are seeking or having treatment, or in post-treatment recovery for the use of psychoactive substances. Interventions are any psychological, behavioural or pharmacological treatments used to treat tobacco use. Outcome measures are any that quantitatively report abstinence or reductions in participant tobacco consumption. Key details and tobacco-related outcomes from included studies will be extracted and tabulated before being narratively synthesised. The systematic review protocol has been developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. ETHICS AND DISSEMINATION Ethics approval is not required. Findings will be disseminated via peer-reviewed literature, conference presentations, media and social media. PROSPERO REGISTRATION NUMBER CRD42018108777.