Roll-to-roll (R2R) manufacturing processes demand precise control of web or yarn velocity and tension, alongside robust mechanisms for handling system failures. This paper presents an integrated approach combining high-performance control with reliable fault detection for an experimental R2R system. A model-based cascade control strategy is designed, incorporating system identification, radius compensation for varying roll diameters, and a Kalman filter to mitigate load sensor noise, ensuring accurate regulation of yarn velocity and tension under normal operating conditions. In parallel, a data-driven fault detection layer uses Gaussian Process Regression (GPR) models, trained offline on healthy operating data, to predict yarn tension and motor speeds. During operation, discrepancies between measured and GPR-predicted values that exceed predefined thresholds trigger an immediate shutdown of the system, preventing material loss and equipment damage. Experimental trials demonstrate tension regulation within ±0.02 N and velocity errors below ±5 rad/s across varying roll diameters, while yarn-break and motor-fault scenarios are detected within a single sampling interval (<100 milliseconds) with zero false alarms. This study validates the integrated system’s capability to enhance both the operational precision and resilience of R2R processes against critical failures.