Individually, sleep deprivation and sub-chronic tramadol exposure have been reported to impair visual processes, however the underlying mechanisms of their combined effects are largely unknown. Thus, this study investigated the role of tramadol hydrochloride on lipid-immune activities in the ocular tissue and visual cortex of sleep-deprived periadolescent rats. Sixty female periadolescent Wistar rats were either sleep-deprived with or without tramadol treatment. Following euthanasia, brain and whole eye tissues were collected for biochemical and immunohistochemical assays. Results revealed impaired ocular tissue lipid profile following sleep deprivation (SD). Sleep deprivation also induced lipid peroxidation; upregulated apolipoprotein E (ApoE), and nuclear factor kappa B (NF-κB) 1 levels in the ocular tissue. Furthermore, chronic SD exposure triggered gliosis with marked increase in astrocyte and microglia counts in the visual cortex. However, treatment with tramadol restored ocular tissue lipid function markers, downregulated ocular tissue NF-κB levels, as well as ameliorated sleep deprivation-induced gliosis in the visual cortex. Taken together, this study demonstrates the role of tramadol in improving inflammatory processes and lipid homeostasis in the visual system by modulating ocular tissue ApoE and NF-κB signalling, and attenuating gliosis in the visual cortex of sleep-deprived rats.