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Brain aging is characterized by cognitive decline and memory deficits that could be the result of oxidative stress and impaired cholinergic function. Several recent studies have suggested that higher intake and blood levels of omega-3 fatty acids may help to reduce the risk of age-related cognitive decline, dementia, and Alzheimer’s disease. The major dietary sources of these fatty acids are fish and shellfish from both salt water and fresh water. EPA and DHA can also be synthesized from the elongation and desaturation of alpha-linolenic acid, which is present in some vegetable oils. Oxidative stress significantly contributes to neuronal damage seen in cases of cognitive impairment and Alzheimer’s disease by depleting the brain of vulnerable, highly unsaturated fatty acids (e.g., EPA and DHA). Some researchers suggest that by replenishing brain cells with EPA and DHA via higher intake levels, individuals may help protect themselves against cognitive decline to a significant degree. These findings prompted us to investigate the effects of daily, 7-day, oral administration of Citrullus vulgaris seed oil on learning and memory by interoceptive behavioral models (passive avoidance test and elevated plus maze), their brain AChE activity, and oxidative status. Whole-brain homogenates were collected for examination of brain oxidative markers and acetylcholinesterase (AChE) activity. Results showed that the short-term supplementation of both healthy adult and aged mice significantly exhibited improvement in learning and memory in the passive avoidance test and attenuated brain oxidative stress markers. Furthermore, AChE activity was significantly decreased only in adult mice. Thus, we showed, for the first time, the significant cognitive enhancement conferred by C. vulgaris seed oil administration in mice is more closely related to antioxidant reinforcement.