Flexible wearable sensors can detect analytes continuously, in real time, and non-invasively, and their application in human health monitoring has received great attention. However, traditional sensors suffer from insufficient biocompatibility, wearing discomfort, and low detection sensitivity, so hydrogel is introduced as a sensor patch to improve the contact between skin and sensor, and combined with surface-enhanced Raman spectroscopy (SERS) technology for rapid and sensitive analysis of biomarkers in sweat. Here, a flexible SERS wearable sensor based on a sulfonated cellulose nanocomposite hydrogel (S-CNF-Ag NPs/PAA) was developed. The hydrogel was prepared by photo-crosslinking of sulfonated cellulose silver nanocomposites (S-CNF-Ag NPs) with acrylic acid (AA), which is a quick and easy preparation process. The network structure of hydrogel can retain small molecules and adsorb sweat through hydrophilic groups, which diffuse sweat into the hydrogel and can effectively collect the analyses in sweat. The introduction of cellulose and silver nanoparticles not only provides excellent mechanical and adhesive properties (toughness of ∼3790 kJ/m3, interfacial toughness of ∼116.23 J/m2), but also good antimicrobial properties and biocompatibility. The SERS technology enabled the quantitative analysis of metabolites in sweat (the detection limits for urea and uric acid were 63.1 μM and 3.98 μM, respectively) and real-time monitoring of pH. S-CNF-Ag NPs/PAA sensor maintained excellent sensitivity, stability and mechanical properties during the detection process, effectively expanding the application of hydrogels in flexible SERS sensing and human health detection.