<p>Periodontal inflammation, such as gingivitis, involves neutrophil infiltration and elevated myeloperoxidase (MPO) activity, leading to excessive reactive oxygen species (ROS) that damage cellular structures, including proteins and lipids. In the oral cavity, oxidative stress may worsen due to local iron release from microbleeding, promoting tissue destruction and gingival recession. This study evaluated the protective effects of orange peel aqueous extract (OPE) and hesperidin (HSP) against iron-induced oxidative damage in human plasma. Additionally, it investigated their in vitro and in vivo anti-inflammatory effects upstream, via inhibition of neutrophil degranulation, and downstream, by reducing MPO activity released in saliva and in an acute inflammation model (λ-carrageenan-induced paw edema in rats). OPE and HSP attenuated FeSO₄-induced lipid peroxidation, with IC₅₀ values of 20.37 ± 5.29 µg/mL and 9.07 ± 2.25 µM, respectively, and inhibited protein carbonyl formation (IC₅₀ values of 49.44 ± 4.64 µg/mL for OPE and 72.93 ± 49.64 µM for HSP), with strong radical scavenging (DPPH, ABTS, and FRAP assays). MPO release was significantly inhibited (maximal inhibition: 47.35 ± 2.65% for OPE, 46.97 ± 0.72% for HSP), and HSP reduced salivary MPO activity dose-dependently (IC₅₀ of 40.9 ± 17.2 µM). Molecular docking confirmed stable binding of HSP and the MPO active site (-13.2 kcal/mol). In vivo, OPE and HSP reduced paw edema, with inhibition rates of 75.26 ± 8.51% and 61.33 ± 12.02%, respectively. These findings highlight the OPE and HSP therapeutic potential as natural modulators of periodontal inflammation and systemic oxidative stress, supporting their development as safe, plant-based anti-inflammatory agents.</p> Graphical abstract <p>A visual representation summarizes the main steps of the experimental procedure applied. Created with BioRender.</p> <p></p>