Background. The aim of this study was the clinical and laboratory evaluation of using polycaprolactone (PCL) nanofibers loaded with oxytetracycline hydrochloride (OTC) and zinc oxide (ZnO) as an adjunct to mechanical therapy in managing stage II grade A periodontitis patients concerning GCF lipocalin2- levels. Methods. Fifty stage II grade A periodontitis patients (27 women and 23 men, with an age range of 30‒60) were enrolled in the study. The patients were randomly assigned to five equal groups and treated with scaling and root planing (SRP), followed by local application of PCL nanofibers: group I: SRP + PCL loaded with OTC and ZnO, group II: SRP + PCL loaded with OTC, group III: SRP + PCL loaded with ZnO, group IV: SRP + unloaded PCL, and group V: SRP alone. Additionally, 10 healthy subjects with healthy periodontium (group VI) (age- and gender-matched) served as the negative control. Nanofibers were applied in the selected pockets of periodontitis patients in groups I to IV once weekly for two months. All the participants were examined clinically by assessing periodontal indices (gingival index, plaque index, pocket depth, and clinical attachment level), and biochemically by assessing GCF lipocalin-2 levels. Results. Compared to controls, periodontitis groups (I, II, III, IV, and V) showed significant elevation of both clinical parameters and GCF lipocalin2- levels at baseline. In addition, these parameters improved significantly after treatment, which was more pronounced in groups I, II-, and III) compared to groups IV and V. However, it did not reach normal values. Conclusion. In association with SRP, PCL nanofibers loaded with OTC and ZnO had beneficial therapeutic effects at both clinical and laboratory levels.