Background/Objective: Non-communicable diseases and mental health conditions impose a growing burden on working-age adults, yet prevention strategies remain fragmented and rarely personalized. This study describes the development of an evidence-informed framework integrating multi-domain health assessment and psychological risk stratification to support personalized prevention in adults aged 18–65 years. Methods: National behavioral surveillance data (PASSI 2023–2024) and occupational disease data (INAIL 2024) were examined to inform the framework. Validated assessment instruments were selected across relevant health domains according to their applicability to the target population. A user-centered and participatory design approach was also incorporated into the DELPHI (Digital Engagement for Lifelong Prevention and Health Improvement) project. Results: The epidemiological evidence highlighted persistent behavioral risk factors and social inequalities among working-age adults. The resulting framework comprises seven assessment domains, integrating validated instruments to characterize participants’ health status and modifiable risk factors. Psychological risk indicators were used to define two personalized prevention pathways, “Maintenance” and “Rebalancing”, with periodic reassessment. Conclusions: The DELPHI framework integrates multi-domain health assessment with psychological risk-based personalization to support preventive interventions in working-age adults. The clinical trial is ongoing; its outcomes, usability and effectiveness will be evaluated upon completion of the project.