BackgroundSubstance use disorders and HIV infection have a bidirectional relationship. People who use illicit drugs are at increased risk of contracting HIV/AIDS, and people living with HIV/AIDS are at increased risk of using substances due to disease-related complications like depression and HIV-associated dementia. There is no adequate evidence on the effect of HIV/AIDS and substance use disorder comorbidity-related effects on placental, fetal, maternal and neonatal outcomes globally.Methods and analysisWe will search articles written in the English language until 30 January 2024, from PubMed/Medline, Cochrane Library, Embase, Scopus, Web of Sciences, SUMsearch2, Turning Research Into Practice database and Google Scholar. A systematic search strategy involving AND/OR Boolean Operators will retrieve information from these databases and search engines. Qualitative and quantitative analysis methods will be used to report the effect of HIV/AIDS and substance use disorders on placental, fetal and maternal composite outcomes. Descriptive statistics like pooled prevalence mean and SD will be used for qualitative analysis. However, quantitative analysis outcomes will be done by using Comprehensive Meta-Analysis Software for studies that are combinable. The individual study effects and the weighted mean difference will be reported in a forest plot. In addition to this, the presence of multiple morbidities like diabetes, chronic kidney disease and maternal haemoglobin level could affect placental growth, fetal growth and development, abortion, stillbirth, HIV transmission and composite maternal outcomes. Therefore, subgroup analysis will be done for pregnant women with multiple morbidities.Ethics and disseminationSince systematic review and meta-analysis will be conducted by using published literature, ethical approval is not required. The results will be presented in conferences and published in peer-reviewed journals.PROSPERO registration numberCRD42023478360.