Silk fibroin (SF) with skin-like features and function shows great prospects in wearable electronics and smart dressing. However, the traditional method of loading conductive materials on physical interfaces can easily lead to the detachment of conductive materials, poor mechanical properties, and unstable conductivity, which hinder their practical application. Herein, simple wet spinning was utilized to fabricate multifunctional regenerated silk fibers reinforced with different contents of intrinsically conductive cellulose nanofibril (CNFene). Significant enhancements in fiber homogeneity, thermal stability, conductivity, mechanical strength, and sensing ability were achieved due to more regular orientation of silk fibroin molecules and strong intermolecular interactions with CNFene. The optimized sample (SF1) with high sensitivity (100 ms), excellent washing/rubbing resistance, and superb waterproof properties (22 days) can comprehensively monitor human motion and weak signals. Surprisingly, inspired by the different humidity levels around wounds at different stages of healing, SF1 with favorable humidity sensitivity can be developed as a smart dressing for monitoring wound healing. Therefore, this work provides a simple preparation route of smart high-performance fiber for flexible electronic devices, smart dressing, and underwater smart textiles.