Periodontitis is a dramatic inflammatory disease, representing vigorous interactions between specific causative pathogens and host immune responses resulting in the activation of the destructive inflammatory cascade with the subsequent irreversible destruction of the teeth-supporting apparatus. This study aims to evaluate the effect of using erythropoietin (EPO) injectable hydrogel, as an additional therapeutic option to scaling and root planing (SRP) in the treatment of stage II periodontitis patients, and to assess its effect on the level of osteocalcin and interleukin (IL)-1β in the gingival crevicular fluid (GCF). A total number of 40 patients clinically diagnosed with stage II periodontitis were included. The participants were allocated into two equal groups: study and control groups. Patients in the control group received SRP, while those in the study group received SRP followed by injectable hydrogel containing EPO. Clinical parameters such as plaque index (PI), gingival index (GI), probing pocket depth (PPD), and clinical attachment level (CAL) were assessed at baseline and two months post treatment. GCF samples were collected at baseline and two months post treatment from both groups to analyze GCF IL-1β and osteocalcin levels using enzyme-linked immunosorbent assay (ELISA). Significant reductions in all tested clinical parameters were revealed in both groups in comparison to baseline values. A marked significant reduction in GCF IL-1β level was detected in the study group. However, two months post treatment, the osteocalcin level was decreased significantly in both groups. This preliminary study shows great promise for the local application of EPO hydrogel as an adjunct to SRP for the management of stage II periodontitis.