In the present work, we report on the synthesis of cellulose cotton fibers covalently linked to diclofenac moieties and the evaluation of the anti-inflammatory activity of this new biomaterial. In spite of recent progress in experimental and clinical medicine, the problem of chronic wounds treatment is still debated. In fact, conventional methods are based on the use of ointment-soaked bandages, but several physical and biological factors contribute to making the efficacy of this method quite low. For this reason, we developed the idea to using modified cotton gauzes to prevent inflammation during wound healing. In this light, diclofenac, a nonsteroidal anti-inflammatory drug, was covalently linked to the cellulose backbone of hydrophilic cotton fibers by a heterogeneous synthesis to produce a functionalized biopolymer with a satisfactory degree of substitution and anti-inflammatory activity. Diclofenac was directly linked to fiber microfibril hydroxylic groups using THF with thionyl chloride. The obtained biopolymer was characterized by infrared spectroscopy (FT-IR) to confirm ester linkages. Finally, the anti-inflammatory activity was evaluated in a well-established in vivo model. The results suggested that these biomaterials possess an excellent anti-inflammatory activity in vivo, so they can be efficiently employed in biomedical fields for chronic wound management to ensure a valid protection against inflammation.