We have reported child anxiety sensitivity (CASI) predicts chronic post-surgical pain (CPSP). Here, we evaluated DNA methylation profiles to understand gene-environmental interactions underlying CPSP and CASI, in order to identify shared, enriched, genomic pathways. In 73 prospectively recruited adolescents undergoing spine fusion, preoperative CASI, and pain data over 12 months post-surgery were collected. DNA from peripheral blood of evaluable subjects with (n=16) and without CPSP (n=40) were analyzed using MethylationEPIC arrays. We identified 637 and 2,445 differentially methylated positions (DMPs) associated with CPSP and CASI respectively (p≤0.05). Ingenuity pathway analysis of 39 genes with DMPs for both CPSP and CASI revealed enrichment of several canonical pathways, including GABA receptor (p=0.00016 (CPSP); 0.0008 (CASI)) and Dopamine-DARPP32 Feedback in cAMP (p=0.004 (CPSP) and 0.00003 (CASI)) Signaling. Gene-gene interaction network enrichment analysis revealed participation of pathways in cell signaling, molecular transport, metabolism and neurological diseases (p-value <10-8). Bioinformatic approaches to identify histone marks and transcription factor (TF) binding events underlying DMPs, showed their location in active regulatory regions in pain pathway relevant brain cells. Using Enrichr/Pinet enrichment and Library of Integrated Network-Based Cellular Signatures (LINCS) knockdown signatures, we identified TFs regulating genes with DMPs in association with CPSP and CASI. In conclusion, we identified epigenetically enriched pathways associated with CPSP and anxiety sensitivity in children undergoing surgery. Our findings support GABA hypofunction and Dopamine-DARPP32 pathway's roles in emotion/reward and pain. This pilot study provides new epigenetic insights into the pathophysiology of CPSP, and a basis for future studies in biomarker development and targetable interventions. Perspective: Differential DNA methylation in regulatory genomic regions enriching shared neural pathways were associated with chronic post-surgical pain and anxiety sensitivity in adolescents undergoing spine surgery. Our findings support GABA hypofunction and Dopamine-DARPP32 pathway's roles in emotion/reward contributing to behavioral maintenance of pain 10-12 months after surgery.