Background: Polycythemia vera (PV), the most common myeloproliferative neoplasm, is driven by JAK2 mutations and often coexists with metabolic syndrome (MS), a major cardiovascular risk factor. Few studies have examined oxidative stress as a potential link between PV and MS. Research design and methods: This observational case–control study included 36 PV patients (15 with MS) and 40 healthy volunteers between 2017 and 2023. Diagnosis followed 2016 WHO criteria. Patients with abnormal hematologic values, organ dysfunction, elevated CRP, or confounding comorbidities were excluded. Oxidative stress was assessed by spectrophotometric measurement of total antioxidant status (TAS) and total oxidant status (TOS). Results: TOS levels were significantly higher in PV–MS patients compared to PV alone (p < 0.05), and oxidative stress markers overall were elevated versus healthy controls (p < 0.05). No significant differences in TAS or TOS were observed between ELN high- and low-risk groups or among patients receiving hydroxyurea, aspirin, metformin, ACE inhibitors, and untreated patients (p > 0.05). Conclusions: Oxidative stress is markedly elevated in PV patients with MS, supporting a pathophysiological link between the two conditions. These findings highlight the importance of considering oxidative stress in the clinical evaluation of PV patients with metabolic syndrome.