Periodontitis, initiated by the subgingival biofilm and modified by the individual’s inflammatory/immune response, has been associated with vascular dysfunction. To analyze microcirculation indices in periodontal tissues and determine the activity of the enzymatic component of antioxidant defense and humoral immunity factors, a single-blind non-invasive clinical trial was realized. Forty subjects, aged from 30 to 65 years, with moderate to severe chronic periodontitis (chronic generalized periodontitis, CGP) vs. 40 subjects as periodontally healthy were recruited. Information such as capillary diameter, capillary blood flow velocity, concentration of pro- and anti-inflammatory cytokines in serum, vascular endothelial growth factor, and enzymatic component of antioxidant protection were taken. The revealed microcirculatory dysfunctions in patients with CGP clearly demonstrate the progressive disorder of periodontal tissue perfusion and oxygenation, the presence of increased vascular permeability and functional failure of the microvascular system in the lesion. Cytokine profile of CGP patients’ blood serum demonstrated a significant increase of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), IL-4 levels as well as statistically significant decrease of IL-1ra, IL-10 concentration. Participants with CGP demonstrated a dominant superiority of IgM and IgG levels. In conclusion, these results contribute to a better understanding of potential correlation between microvascular changes and local and systemic markers of inflammation.