Abstract Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by difficulties in communication, social interaction, and repetitive behaviors. Considering its multifactorial origin and multisystem involvement, this single-case report applies a complex naturopathic intervention—the Katia Dolle Method® (KDM)—integrating immunonutrition, targeted supplementation, parental coaching, structured neurostimulation, and periodic biological monitoring over 21 months. A 4-year-old girl diagnosed with moderate–severe ASD (baseline ATEC = 112) underwent the KDM program (March 2023–November 2024). Outcomes were tracked with ATEC, DP-3, and SENA, alongside blood/urine/stool biomarkers. Results show a reduction of ASD severity from severe to mild (ATEC = 16, −85.7%) in 21 months, and a DP-3 General Development Index increase from 62 to 91 (≈ +29 points, ~2.4 SD) in the last 12 months, exceeding maturational expectations (“catch-up” effect). SENA indices improved consistently (problem indices decreased, personal resources increased). No regressions or adverse effects were observed. This case illustrates the clinical applicability of a complex, multimodal naturopathic approach for ASD within a PNIE framework and supports the need for prospective controlled studies. Figures and underlying data are provided as supplementary materials. Peer review statement This manuscript received an external verbal peer review by María José Sala Frau, Vicepresidencia en Formación, Investigación y Didáctica del Comité Científico de la OCN-FENACO, on September 9, 2025. The discussion covered methodology, statistics, ethics, and reporting standards. No written review files are available; the authors incorporated the feedback provided orally. This Zenodo record is deposited as a preprint/report; the peer review was conducted independently of Zenodo and outside a journal workflow. CRediT author statement Katia Dolle: Writing – original draft; Investigation; Visualization. Aitor Garcia Galardi: Conceptualization; Methodology; Supervision; Writing – review & editing. Ethics/Consent Parents provided written informed consent for publication. Identities are concealed. Conflict of Interest None declared. Funding No external funding; professional time and analyses supported by the Katia Dolle Foundation. Data & materials availability. High-resolution figures and underlying CSV data for DP-3 and SENA are available within this record (figures/, supplementary/).