The integration of wearable smart garments with multiple sensors has gained momentum, enabling real-time monitoring of users’ vital parameters across various domains. This study presents the development and validation of an instrumented smart shirt for risk prevention in workplaces designed to enhance worker safety and well-being in occupational settings. The proposed smart shirt is equipped with sensors for collecting electrocardiogram, respiratory waveform, and acceleration data, with signal conditioning electronics and Bluetooth transmission to the mobile application. The mobile application sends the data to the cloud platform for subsequent Preventive Risk Index (PRI) extraction. The proposed SenseRisc system was validated with eight healthy participants during the execution of different physically exerting activities to assess the capability of the system to capture physiological parameters and estimate the PRI of the worker, and user subjective perception of the instrumented intelligent shirt.