Background: Patent foramen ovale (PFO) is associated with cryptogenic stroke, but mechanisms beyond paradoxical embolism remain unclear. Inflammation, fibrosis-related remodeling, and nitrosative stress may contribute to vascular vulnerability in these patients. The aim of this study was to evaluate inflammatory, fibrotic, and nitrosative biomarker profiles in patients with PFO and prior cryptogenic stroke and to determine whether these patients exhibit coupled inflammatory fibrotic nitrosative activation. Methods: This prospective, observational, single-center study included 92 patients aged <55 years with PFO and prior cryptogenic stroke and 56 age-matched controls without PFO and cerebrovascular events. Circulating interleukin-18 (IL-18), galectin-3, and 3-nitrotyrosine (3-NT) levels were measured using ELISA assays. Correlation and linear regression analyses were performed. Results: Compared with controls, patients with PFO had higher galectin-3 (11.87 vs. 10.36 ng/mL; p = 0.015), IL-18 (268.0 vs. 121.0 pg/mL; p < 0.001), and 3-NT (48.5 vs. 41.8 ng/mL; p = 0.046). Significant correlations were observed between IL-18 and galectin-3 (r = 0.565), IL-18 and 3-NT (r = 0.425), and galectin-3 and 3-NT (r = 0.292) (all p ≤ 0.002). Conclusions: Patients with PFO and prior cryptogenic stroke exhibit a distinct biomarker profile consistent with coupled inflammatory–fibrotic–nitrosative activation, suggesting a potential non-mechanical component of stroke susceptibility.