Hydroxytyrosol (HT; 3,4-dihydroxyphenyl ethanol) is an important functional polyphenol in olive oil. Our study sought to evaluate the protective effects and underlying mechanisms of HT on obesity-induced cognitive impairment. A high-fat and high-fructose-diet-induced obese mice model was treated with HT for 14 weeks. The results show that HT improved the learning and memory abilities and enhanced the expressions of brain-derived neurotrophic factors (BDNFs) and postsynaptic density proteins, protecting neuronal and synaptic functions in obese mice. Transcriptomic results further confirmed that HT improved cognitive impairment by regulating gene expression in neural system development and synaptic function-related pathways. Moreover, HT treatment alleviated neuroinflammation in the brain of obese mice. To sum up, our results indicated that HT can alleviate obesity-induced cognitive dysfunction by enhancing BDNF expression and alleviating neuroinflammation in the brain, which also means that HT may become a potentially useful nutritional supplement to alleviate obesity-induced cognitive decline.