Callous-unemotional (CU) traits are characterized by a lack of guilt and empathy, restricted affect, and low concern about performance, and are increasingly recognized as co-occurring with substance use in youth. However, there is mixed evidence concerning whether they make a unique contribution to substance use. This systematic review and meta-analysis sought to quantify the association between CU traits and substance use in childhood, accounting for potential moderators including sample characteristics (age, gender, community versus clinical/forensic samples), CU traits measure and informant, and study design (cross-sectional or longitudinal). Separate meta-analyses were conducted for alcohol, cannabis, and a substance use composite. Small, significant associations were found between CU traits and alcohol (θ = 0.17), cannabis (θ = 0.17) and the substance use composite (θ = 0.15), which were present in both community and clinical/forensic samples. Findings suggest that CU traits co-occur with a range of substance use problems, and that CU traits should be considered in assessments of youth presenting with substance use problems regardless of the nature of the setting. •Callous unemotional CU traits relate to youth antisocial behavior and substance use.•We quantified this link considering study design/methods and sample characteristics.•CU traits correlated positively with alcohol, cannabis, and a substance composite.•The small effect sizes did not differ based on sex, age, sample type or methodology.•Methodological consistency is needed to facilitate our understanding of this link.