<p>Keratoconus is a progressive corneal disorder characterized by thinning and steepening of the cornea, leading to visual impairment and reduced quality of life. Although epithelium-off corneal cross-linking has emerged as the gold-standard therapy, it can be associated with postoperative pain, delayed healing, and increased risk of complications due to removal of the corneal epithelium. To overcome these limitations, epithelium-on cross-linking was developed as a less invasive alternative. In epithelium-on cross-linking, three essential components must be present to maximize the photochemical reaction: oxygen, riboflavin formulation with permeation enhancers, and high-irradiance pulsed ultraviolet-A (UV-A) light. Oxygen plays an especially critical rate-limiting role, as it interacts with riboflavin and UV-A irradiation to produce the reactive oxygen species (ROS) that promote covalent cross-links, thereby strengthening the corneal stroma. Given that the intact epithelium during epithelium-on cross-linking can act as a barrier to oxygen diffusion, in addition to riboflavin penetration, enhancing oxygen availability during epithelium-on cross-linking has been shown to improve treatment outcomes. Oxygen-enriched epithelium-on cross-linking is poised to emerge as a mainstay therapy for keratoconus. This narrative review examines the influence of oxygen supplementation, a key rate-limiting factor, in enhancing the efficacy of epithelium-on cross-linking.</p>