Objective: This study aimed to elucidate the genetic, epigenetic, and environmental determinants of pediatric congenital heart disease, a prevalent congenital anomaly affecting approximately 1% of live births globally. Methodology: The study was conducted as a case-control observational investigation, wherein two hundred pediatric patients clinically diagnosed with CHD were compared against three hundred age-matched healthy controls with no familial history of CHD. Participants were selected based on well-defined inclusion and exclusion criteria to ensure the reliability of findings. Comprehensive demographic, clinical, and genetic histories were meticulously collected through medical records and direct patient interviews. Peripheral blood samples were obtained from all participants, followed by whole-exome sequencing and targeted genetic screening to identify deleterious genetic variants associated with CHD. Bioinformatics tools and computational modeling were employed to annotate, map, and analyze the identified mutations, integrating comparative statistical analyses to infer their pathogenic implications. Additionally, epigenetic profiling, including DNA methylation and histone modification analyses, was performed to examine non-genetic regulatory mechanisms. The role of maternal environmental factors, such as teratogenic exposure, maternal diabetes, and folate deficiency, was assessed through gene-environment interaction modeling to evaluate their contribution to CHD susceptibility. Results: The study identified several pathogenic genetic variants implicated in CHD, with NKX2-5, GATA4, TBX5, NOTCH1, CHD7, and SMAD3 mutations emerging as the most frequently observed. NKX2-5 missense mutations were detected in 20% of CHD patients, linked to atrial septal defects and conduction abnormalities. GATA4 frameshift mutations were identified in 15% of cases, with a strong correlation to ventricular septal defects and Tetralogy of Fallot. TBX5 nonsense mutations, occurring in 12% of affected individuals, were significantly associated with atrioventricular septal defects and Holt-Oram syndrome. The study further revealed a substantial burden of de novo mutations in CHD7, NOTCH1, and SMAD3, reinforcing their critical role in cardiac valve formation and outflow tract development. Beyond genetic variations, epigenetic modifications were identified as significant contributors to CHD pathogenesis. Aberrant DNA methylation patterns, observed in 40% of CHD patients, led to the silencing of key cardiac transcription factors, particularly NKX2-5 and GATA4, thereby disrupting normal cardiac morphogenesis. Histone acetylation modifications affected TBX5 and SMAD3, altering their transcriptional activity and developmental regulation. Additionally, non-coding RNA dysregulation, affecting NOTCH1 and CHD7, was observed in 25% of CHD cases, implicating miRNA-mediated post-transcriptional regulation in disease progression. The study also confirmed significant gene-environment interactions, wherein maternal diabetes, teratogenic exposures, folate deficiency, and prenatal infections markedly influenced CHD risk. Maternal diabetes (OR = 3.5, p < 0.001) was strongly associated with mutations in GATA4 and TBX5, suggesting that hyperglycemia-induced oxidative stress altered fetal cardiac gene expression. Teratogenic exposures (OR = 4.2, p < 0.005) increased the prevalence of CHD7 and NOTCH1 mutations, reinforcing the role of prenatal toxins in disrupting cardiac development. Folate deficiency (OR = 2.8, p < 0.01) was linked to NKX2-5 and SMAD3 mutations, highlighting the necessity of maternal nutritional optimization during pregnancy. Conclusion: This study reaffirmed the multifactorial and polygenic nature of CHD, consolidating existing research while introducing novel genetic variants and epigenetic mechanisms contributing to disease susceptibility. The findings underscored the pivotal role of monogenic mutations, de novo variants, and gene-environment interactions in shaping CHD pathogenesis. By integrating genomic sequencing, epigenetic profiling, and maternal risk factor analyses, the study provided a comprehensive framework for understanding CHD etiology. The identification of pathogenic genetic variants highlighted the potential for early genetic screening, enabling personalized risk assessments and tailored interventions. Furthermore, the epigenetic findings suggested that targeted therapies aimed at reversing DNA methylation abnormalities or modulating histone modifications could hold promise for future treatment strategies. Considering these findings, future research should aim to validate these genetic and epigenetic associations across diverse populations while exploring the therapeutic potential of gene-editing technologies, such as CRISPR-Cas9, for CHD correction. These insights paved the way for the integration of genomic data into precision medicine frameworks, enhancing early diagnostics, individualized management, and therapeutic innovations for congenital heart disease.