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Abstract Introduction The incidence of early-onset colorectal cancer (EOCRC) is rising rapidly, with disproportionate health burdens falling on populations that experience both the steepest increases and the poorest outcomes. The phosphoinositide 3-kinase (PI3K) signaling pathway is a key oncogenic driver in colorectal cancer (CRC), influencing tumor growth, survival, and therapeutic resistance. Despite its biological significance, the role of PI3K pathway alterations in EOCRC remains poorly understood—particularly in underrepresented populations—due to limited diversity in genomic datasets and a lack of tools for integrative, pathway-specific analysis. To address this gap, we developed AI-HOPE-PI3K, a conversational artificial intelligence (AI) system designed to streamline clinical-genomic integration and enable real-time, population-aware analysis of PI3K dysregulation in CRC. Methods AI-HOPE-PI3K is built on a fine-tuned biomedical LLaMA 3 large language model (LLM) and supports natural language queries that are translated into executable statistical pipelines. The platform harmonizes and integrates data from cBioPortal, encompassing key clinical features such as age, race/ethnicity, MSI status, tumor site, stage, treatment history, and survival outcomes. It automates cohort construction, survival modeling, mutation frequency comparison, and odds ratio analysis, delivering interpretive visual and tabular outputs. Validation was performed through the replication of known PI3K-related associations and comparative benchmarking against existing bioinformatics platforms. Results AI-HOPE-PI3K enabled real-time interrogation of CRC datasets, producing interpretable results without the need for programming. Among EOCRC patients, the frequency of PI3K alterations was similar across different population cohorts. However, colon tumors harboring PI3K alterations were associated with significantly worse survival compared to rectal tumors (p = 0.0177). High tumor mutational burden (TMB) predicted improved survival in FOLFIRI-treated CRC patients (p = 0.0032) and was enriched for MTOR mutations. Among MSI-high patients receiving pembrolizumab, survival did not differ significantly by PIK3CA mutation status. Notably, INPP4B mutations were significantly enriched in H/L EOCRC patients (OR = 3.57, p = 0.005), indicating a potential ancestry-linked biomarker. Analyses stratified by age and stage in PTEN- and PI3K-altered CRC cohorts revealed context-dependent trends in survival. Conclusions AI-HOPE-PI3K is a first-in-class, conversational AI platform that enables natural language–based, PI3K-pathway-specific analysis of CRC genomics. By integrating multi-institutional datasets with clinical annotations, it democratizes access to complex analyses and enables equitable exploration of PI3K biology. The system reliably reproduced established findings and uncovered novel, population-specific genomic insights—particularly among H/L EOCRC patients. AI-HOPE-PI3K demonstrates the power of AI-driven platforms to advance precision oncology and address disproportionate health burdens through scalable, real-time, and hypothesis-driven clinical-genomic investigation.