Tobacco and cannabis are commonly co-used, and evidence for the influence of co-use on quit outcomes for either substance is mixed. We sought to determine the efficacy of tobacco and/or cannabis use interventions delivered to co-users on cannabis and tobacco use outcomes. Systematic review with meta-analysis and narrative review, using five databases and author requests for co-use data. Controlled and uncontrolled intervention studies focusing on treatment of tobacco and/or cannabis use assessing use of both pre- and post-intervention were included. Prevention interventions were excluded. Bayesian meta-analysis was used across four outcome measures: risk ratio for tobacco and cannabis cessation post-intervention separately; standardized mean change for tobacco and cannabis reduction post-intervention separately. Narrative reporting of the same outcome measures in non-randomized clinical trials (non-RCTs) and quality assessment of all included studies were conducted. Twenty studies (12 RCTs and eight uncontrolled) were included. Bayesian meta-analysis with informative priors based on existing data of 11 RCTs (six single-substance, five multi-substance interventions) delivered to co-users (n=up to 1117) showed weak evidence for an effect on cannabis cessation [risk ratio (RR)=1.48, credibility interval (CrI)=0.92, 2.49, eight studies] and no clear effect on tobacco cessation (RR=1.10, CrI=0.68, 1.87, nine studies). Subgroup analysis suggested that multi-substance interventions might be more effective than cannabis-targeted interventions on cannabis cessation (RR=2.19, CrI=1.10, 4.36 versus RR=1.39, CrI=0.75, 2.74). A significant intervention effect was observed on cannabis reduction (RR=0.25, CrI=0.03, 0.45, nine studies) but not on tobacco reduction (RR=0.06, CrI=-0.11, 0.23, nine studies). Quality of evidence was moderate, although measurement of co-use and cannabis use requires standardization. Uncontrolled studies targeting both cannabis and tobacco use indicated feasibility and acceptability. Single and multi-substance interventions addressing tobacco and/or cannabis have not shown a clear effect on either tobacco or cannabis cessation and reduction among co-users. However, dual substance interventions targeting tobacco and cannabis appear feasible.