BackgroundDigital cognitive behavioral therapy (CBT) interventions can effectively prevent and treat depression and anxiety, but engagement with these programs is often low. Although extensive research has evaluated program use as a proxy for engagement, the extent to which users acquire knowledge and enact skills from these programs has been largely overlooked.ObjectiveThis study aimed to investigate how skill enactment and knowledge acquisition have been measured, evaluate postintervention changes in skill enactment and knowledge acquisition, examine whether mental health outcomes are associated with skill enactment or knowledge acquisition, and evaluate predictors of skill enactment and knowledge acquisition.MethodsPubMed, PsycINFO, and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) published between January 2000 and July 2022. We included RCTs comparing digital CBT with any comparison group in adolescents or adults (aged ≥12 years) for anxiety or depression. Eligible studies reported quantitative measures of skill enactment or knowledge acquisition. The methodological quality of the studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for RCTs. Narrative synthesis was used to address the review questions.ResultsIn total, 43 papers were included, of which 29 (67%) reported a skill enactment measure and 15 (35%) reported a knowledge acquisition measure. Skill enactment was typically operationalized as the frequency of enacting skills using the completion of in-program activities (ie, formal skill enactment; 13/29, 45%) and intervention-specific (9/29, 31%) or standardized (8/29, 28%) questionnaires. Knowledge measures included tests of CBT knowledge (6/15, 40%) or mental health literacy (5/15, 33%) and self-report questionnaires (6/15, 40%). In total, 17 studies evaluated postintervention changes in skill enactment or knowledge acquisition, and findings were mostly significant for skill enactment (6/8, 75% of the studies), CBT knowledge (6/6, 100%), and mental health literacy (4/5, 80%). Of the 12 studies that evaluated the association between skill enactment and postintervention mental health outcomes, most reported ≥1 significant positive finding on standardized questionnaires (4/4, 100%), formal skill enactment indicators (5/7, 71%), or intervention-specific questionnaires (1/1, 100%). None of the 4 studies that evaluated the association between knowledge acquisition and primary mental health outcomes reported significant results. A total of 13 studies investigated predictors of skill enactment; only type of guidance and improvements in psychological variables were associated with increased skill enactment in ≥2 analyses. Predictors of knowledge acquisition were evaluated in 2 studies.ConclusionsDigital CBT for depression and anxiety can improve skill enactment and knowledge acquisition. However, only skill enactment appears to be associated with mental health outcomes, which may depend on the type of measure examined. Additional research is needed to understand what types and levels of skill enactment and knowledge acquisition are most relevant for outcomes and identify predictors of these constructs.Trial RegistrationPROSPERO CRD42021275270; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=275270