<p>The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood–brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state between normal aging and dementia, is characterized by early neuroinflammation and neuronal injury, yet how systemic markers reflect central pathology is poorly understood. In this study, we enrolled 74 participants, including 37 MCI patients and 37 cognitively normal controls. Based on the CSF/serum albumin ratio, subjects were classified into four groups—NC (cognitively normal with intact BBB), NMCI (MCI with intact BBB), BC (cognitively normal with BBB disruption), and BMCI (MCI with BBB disruption)—and further grouped as BBB-intact or BBB-disrupted. Serum and cerebrospinal fluid (CSF) levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (Nf-L) were measured using enzyme-linked immunosorbent assay. Spearman correlation analysis was applied to examine peripheral–central associations. No significant correlations were observed in NC or NMCI groups. A moderate serum–CSF GFAP correlation was found in the BC group (r = 0.446, <i>P</i> = 0.033), which became markedly stronger in the BMCI group (r = 0.753, <i>P</i> &lt; 0.001). In the BBB-disrupted group, significant correlations were detected for GFAP (r = 0.652, <i>P</i> &lt; 0.001), IL-4 (r = 0.412, <i>P</i> = 0.003), IL-6 (r = 0.296, <i>P</i> = 0.035), and TNF-α (r = 0.352, <i>P</i> = 0.011), with GFAP showing the strongest association. In contrast, within the BBB-intact group, only serum–CSF IL-6 correlation reached significance (r = 0.469, <i>P</i> = 0.024). These findings suggest that BBB disruption markedly enhances peripheral–central biomarker associations, especially for GFAP, highlighting the regulatory role of BBB integrity in linking systemic inflammation, neuronal injury, and MCI pathophysiology.</p>