The relationships of demodex density with systemic oxidative stress, inflammatory response, and clinical severity in rosacea are not clear. This study aimed to (a) analyze the levels of systemic oxidative stress, antioxidant capacity, inflammatory parameters, and matrix metalloproteinases (MMPs) in systemic circulation in patients with rosacea, (b) identify the relationship between mite density and both oxidative stress and inflammation, and (c) investigate the role of photoaging and sebum secretion in etiopathogenesis. Forty patients with rosacea and 40 age-, sex-, and skin phenotype-matched healthy volunteers were included in the study. Clinical disease severity of the patients was determined. Sebum levels were measured in both the groups, and photoaging was evaluated. Reflectance confocal microscopy was used to calculate demodex density. Serum total antioxidant capacity (TAC), total oxidant capacity (TOC), myeloperoxidase (MPO), MMP-1, MMP-9, arylesterase (ARES), interleukin-1 beta (IL-1 beta), paraoxonase-1 (PON-1), and tumor necrosis factor-alpha (TNF-alpha) levels were also analyzed. The patients with rosacea had significantly higher serum TOC and lower TAC levels (p < 0.001). The serum ARES and PON-1 levels were significantly lower (p = 0.045 and p < 0.001, respectively); however, the serum levels of MMP-1, MMP-9, IL-1 beta and MPO were higher in the patient group. Demodex parameters were higher in the patient group compared to the control group. There was no significant correlation between the number of mites and disease severity. In addition, the number of mites was not correlated with the serum levels of TAC, TOC, OSI, MPO, MMP-1, MMP-9, ARES, PON-1, TNF-alpha, and IL-1 beta. However, sebum levels were directly proportional to the number of mites. Photoaging severity was similar between the patients and control subjects. The changing sebaceous microenvironment in rosacea leads to an increase in the number of demodex mites. However, increased demodex density does not alter disease severity, level of oxidative stress, or inflammation. Although none of the patients with rosacea had any underlying systemic disease, patients' systemic oxidative stress and inflammation parameters were found high in systemic circulation. It is assumed that the patients with rosacea are more prone to systemic diseases.