Ischemic and/or hypoxic ocular diseases lack adequate, effective mitigative approaches and an understanding of the fundamental causes of ischemia-induced tissue damage. In this work, we introduce a plant-derived exosome-coated niosome oxygen nanobubble (E-NON), consisting of a gaseous oxygen core encapsulated within dual shells. The niosome inner shell is composed of Pluronic F-127, polysorbate 80, and medium chain triglyceride (MCT) oil, all of which are FDA approved for ophthalmic indications. The outer shell consists of exosomes derived from (ashwagandha) fruits, which are known for their antioxidant and anti-inflammatory properties. The hydrodynamic diameter of conceived E-NONs is 85.6 ± 14.4 nm with a zeta (ζ)-potential of -19.3 ± 0.8 mV, and oxygen loading capacity of 56.4 ± 0.9 mg/L. The E-NON formulation was stable in sealed glass vials for up to 3 months at 4 °C and yields a controlled release profile extending up to 16 h under hypoxic conditions. The therapeutic efficacy of E-NONs for hypoxia mitigation was evaluated in retinal epithelium (ARPE19) and uveal melanoma (MP46) cell lines, both demonstrating excellent hypoxia recovery. Moreover, RT-qPCR results verified downregulation of genes related to hypoxia (HIF-1α, VEGF-A, EPO, PAI-1) and oxidative stress (Nrf2, NQO1, HO-1) after treatment with 10 (v/v%) E-NONs. Additionally, an in vivo safety evaluation in a rabbit model indicated that the formulation was safe for intravitreal administration. We propose that our novel oxygen delivery platform is an effective tool for hypoxia mitigation and can be utilized to treat ischemic conditions in the eye.