(1) Background: Uveal malignant melanoma is the most common adult eye cancer and presents metabolic reprogramming that affects the tumoral microenvironment by altering the redox balance and producing oncometabolites. (2) Methods: The study prospectively evaluated patients undergoing enucleation surgery or stereotactic radiotherapy for uveal melanoma by following systemic oxidative-stress redox markers serum lipid peroxides, total albumin groups and total antioxidant levels (3) Results: Serum antioxidants and lipid peroxides were elevated from pre-treatment to longer-term follow-up. Antioxidants inversely correlated to lipid peroxides: higher in stereotactic radiosurgery patients pre/6/12/18 months post-treatment (p= 0.001–0.049) versus higher lipid peroxides in enucleation surgery patients pre/after/6 months post-treatment (p= 0.004–0.010). An increased variance in serum antioxidants was observed for enucleation surgery patients (p< 0.001), however enucleation did not increase mean serum antioxidants or albumin thiols; only lipid peroxides were increased post-enucleation (p< 0.001) and at 6-month follow-up (p= 0.029). Mean albumin thiols were increased for 18- and 24-month follow-ups (p= 0.017–0.022). Males who had enucleation surgery presented higher variance in serum determinations and overall higher lipid peroxides values pre/post-treatment and at the 18-month follow-up. (4) Conclusions: Initial oxidative stress-inducing events of surgical enucleation or stereotactic radiotherapy for uveal melanoma are followed by a longer-term inflammatory cascade gradually subsiding at later follow-ups.