Objective: The objective of this work was to design, prepare and evaluate the stability of fenoprofen calcium loaded polymeric nanoparticles with Eudragit RL100. Methods: Nine formulations (F1 to F9) were made by the solvent displacement method using 100 mg fenoprofen calcium, different quantities of Eudragit RL100 (100–300 mg) and PVA (1–3% w/v). The particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, drug loading, percentage yield and in-vitro drug release were evaluated as the qualities of formulations. Drug–excipient compatibility was evaluated by FTIR spectroscopy, particle morphology by SEM and the stability was determined under refrigerated, room temperature and accelerated conditions for a period of three months. Results: Particle size ranged from 168.54 to 265.48 nm, PDI from 0.215 to 0.302, and zeta potential from +18.62 to +30.18 mV. The efficiencies of entrapment were between 68.45% and 88.64% and drug loading ranged from 17.32% to 31.24%. Formulation F6 was selected as the optimized batch, exhibiting a particle size of 198.72 ± 3.15 nm, PDI of 0.215 ± 0.007, zeta potential of +25.83 ± 0.74 mV, entrapment efficiency of 82.16 ± 1.26%, drug loading of 20.35 ± 0.43%, and percentage yield of 83.28 ± 1.35%. Drug release reached 92.85 ± 1.35% at 24 hours. FTIR indicated that there were no significant changes in the spectra, and SEM revealed a major amount of spherical particles with some aggregation. Other conditions failed to maintain the physicochemical characteristics as well as refrigerated storage. Conclusion: The successful formulation of Eudragit RL100 nanoparticles along with the desirable overall properties and sustained release of F6 was observed. The long-term stability and pharmaceutical performance should be determined in further studies.