Diclofenac has a relatively low oral bioavailability (50–60%) and is quickly metabolized with a half-life of less than 1 h. Therefore, the oral therapeutic effect of diclofenac is not optimal. This research developed polyvinylpyrrolidone K30-functionalized silk fibroin nanoparticles as an effective delivery system for diclofenac (FNPs-PVP-DC). The FNPs-DC and FNPs-PVP-DC were formulated by two methods of adsorption and solvent exchange. Depending on the formulation factors, the obtained particles exhibited different properties of nano-scale sizes (400–800 nm), narrow size distribution, negatively charged surfaces (17 to 19 mV), high PVP K30 incorporation (23 %–50 %), pHpzc of ~6.6, and appropriate chemical interactions. Interestingly, particles formulated by the adsorption method showed low drug encapsulation efficiencies of <15%, whereas the solvent exchange method yielded moderate results of ~40%. The FNPs-DC possessed aggregated patterns, while the FNPsPVP-DC were more uniformly distributed. All formulations limited diclofenac release (<20 %) under gastric conditions and sustained its release in the intestinal environment. In in-vivo carrageenan-induced paw edema mice model, the FNPs-PVP-DC demonstrated a 20–30 % higher anti-inflammatory effect and a faster onset of action (within 1 h) compared to pure diclofenac at the same dose (5 mg/kg). These findings suggest that FNPsPVP-DC have promising potential as novel oral anti-inflammatory products.