Background: As digital mental health delivery becomes increasingly prominent, a solid evidence base regarding its efficacy is needed. Objective: This study aims to synthesize evidence on the comparative efficacy of systemic psychotherapy interventions provided via digital versus face-to-face delivery modalities. Methods: We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for searching PubMed, Embase, Cochrane CENTRAL, CINAHL, PsycINFO, and PSYNDEX and conducting a systematic review and meta-analysis. We included randomized controlled trials comparing mental, behavioral, and somatic outcomes of systemic psychotherapy interventions using self- and therapist-guided digital versus face-to-face delivery modalities. The risk of bias was assessed with the revised Cochrane Risk of Bias tool for randomized trials. Where appropriate, we calculated standardized mean differences and risk ratios. We calculated separate mean differences for nonaggregated analysis. Results: We screened 3633 references and included 12 articles reporting on 4 trials (N=754). Participants were youths with poor diabetic control, traumatic brain injuries, increased risk behavior likelihood, and parents of youths with anorexia nervosa. A total of 56 outcomes were identified. Two trials provided digital intervention delivery via videoconferencing: one via an interactive graphic interface and one via a web-based program. In total, 23% (14/60) of risk of bias judgments were high risk, 42% (25/60) were some concerns, and 35% (21/60) were low risk. Due to heterogeneity in the data, meta-analysis was deemed inappropriate for 96% (54/56) of outcomes, which were interpreted qualitatively instead. Nonaggregated analyses of mean differences and CIs between delivery modalities yielded mixed results, with superiority of the digital delivery modality for 18% (10/56) of outcomes, superiority of the face-to-face delivery modality for 5% (3/56) of outcomes, equivalence between delivery modalities for 2% (1/56) of outcomes, and neither superiority of one modality nor equivalence between modalities for 75% (42/56) of outcomes. Consequently, for most outcome measures, no indication of superiority or equivalence regarding the relative efficacy of either delivery modality can be made at this stage. We further meta-analytically compared digital versus face-to-face delivery modalities for attrition (risk ratio 1.03, 95% CI 0.52-2.03; P=.93) and number of sessions attended (standardized mean difference –0.11; 95% CI –1.13 to –0.91; P=.83), finding no significant differences between modalities, while CIs falling outside the range of the minimal important difference indicate that equivalence cannot be determined at this stage. Conclusions: Evidence on digital and face-to-face modalities for systemic psychotherapy interventions is largely heterogeneous, limiting conclusions regarding the differential efficacy of digital and face-to-face delivery. Nonaggregated and meta-analytic analyses did not indicate the superiority of either delivery condition. More research is needed to conclude if digital and face-to-face delivery modalities are generally equivalent or if—and in which contexts—one modality is superior to another.