Specific carotenoid (e.g., β-carotene, lutein, lycopene) has potential benefits for cognitive health demonstrated in both human and animal studies. To mimic the composition of carotenoids in the human diet and to avoid the overdose of any specific carotenoid, we developed a mixture of 6 carotenoids (7.5 mg/(kg·day), including 9.0% α-carotene, 35.8% β-carotene, 12.2% lutein, 1.6% zeaxanthin, 41.0% lycopene and 0.4% β-cryptoxanthin) and investigated its long-term neuroprotective effect and potential mechanism in APP/PS1 mice, a well-established animal model for Alzheimer’s disease. Initiated at 3 months with a total of 4 months’ gavage intervention, the dietary carotenoids mixture was found to alleviate cognitive impairment and amyloid β deposition in the brain (P < 0.05). Consistently, dietary carotenoids mixture restored Nissl bodies and the density of dendritic spines, and increased protein expression of Synapsin and PSD95 in the hippocampus and cortex of APP/PS1 mice (P < 0.05). In addition, carotenoids were also found to reduce oxidative stress and inflammation level and increase autophagy (P < 0.05). Importantly, carotenoids have been shown to up-regulate the expression of silent information regulator 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) in the brain (P < 0.05). Together, long-term intake of dietary carotenoids mixture could alleviate the cognitive deficit in APP/PS1 mice, wherein the SIRT1/BDNF pathway might play an important role. Our findings could contribute to the development of effective dietary and nutritional intervention strategies for delaying neurodegeneration in the aging population.