<p>Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and restricted, repetitive behaviors, yet the comparative effectiveness of pharmacological and nonpharmacological interventions remains unclear. Here we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate interventions targeting core ASD symptoms. PubMed, Embase, PsycINFO and Cochrane databases were searched through April 2025. Eligible studies included randomized trials with active or inactive controls assessing social communication, restricted or repetitive behaviors, or overall symptom severity. Data from 149 trials (<i>N</i> = 9,011), including 69 nonpharmacological studies (<i>n</i> = 2,889) and 217 pharmacological or dietary-supplement studies (<i>n</i> = 6,122), were pooled using random-effects models. The primary outcome was standardized improvement in core symptoms (Hedges’ <i>g</i>). Nonpharmacological interventions showed a significantly larger pooled effect size (<i>g</i> = 0.70; s.e. = 0.071; <i>I</i>² = 75.6%) compared with pharmacological approaches (<i>g</i> = 0.20; s.e. = 0.025; <i>I</i>² = 44.1%), with a significant between-group difference (Δ = 0.43; s.e. = 0.058; <i>P</i> &lt; 0.0001). Moderator analyses indicated that smaller sample size, shorter duration, non-Western settings, clinician-rated outcomes and earlier publication were associated with larger effect sizes; meta-regression identified sample size and publication year as significant predictors. These findings suggest that behavioral and psychosocial interventions demonstrate greater efficacy for core ASD symptoms, while study design and contextual factors substantially influence reported outcomes, highlighting the need for rigorous, well-controlled clinical trials.</p>