A plausible association exists among spicy food consumption, physical activity, and Alzheimer’s disease (AD) or cognitive decline, but it remains poorly investigated. We aimed to examined the association between spicy food and AD-related memory decline or global cognitive decline in older adults under the moderating effect of physical activity. Total 196 non-demented older adults were included. Participants underwent comprehensive dietary and clinical assessments including spicy food intake, AD-related memory, global cognition, and physical activity. The strength of spicy food was stratified into three categories: ‘not spicy’ (reference), ‘low spiciness’, and ‘high spiciness’. Multiple linear regression analyses were performed to examine the relationships between spicy level and cognition. The spicy level was the independent variable in each analysis; it was entered as a stratified categorical variable using the three categories. We found a significant association between a high level of spiciness in food and decreased memory (\documentclass[12pt]{minimal}
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				\begin{document}$$\beta$$\end{document}β− 0.167,p< 0.001) or global cognition (\documentclass[12pt]{minimal}
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				\begin{document}$$\beta$$\end{document}β− 0.122,p= 0.027), but not non-memory cognition. To explore the moderating effects of age, sex, apolipoprotein E ε4 allele-positivity, vascular risk score, body mass index, and physical activity on the associations between spicy level and memory or global cognition, the same regression analyses were repeated including two-way interaction terms between the spicy level and each of the six variables as an additional independent variable. An interactive effect was detected between a high level of spiciness in food and physical activity on the memory (\documentclass[12pt]{minimal}
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				\begin{document}$$\beta$$\end{document}β0.209,p= 0.029) or global cognition (\documentclass[12pt]{minimal}
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				\begin{document}$$\beta$$\end{document}β0.336,p= 0.001). Subgroup analyses showed that the association between a high level of spiciness in food and a lower memory (\documentclass[12pt]{minimal}
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				\begin{document}$$\beta$$\end{document}β− 0.254,p< 0.001) and global score (\documentclass[12pt]{minimal}
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				\begin{document}$$\beta$$\end{document}β− 0.222,p= 0.002) was present only in older adults with low physical activity, but not in older adults with high physical activity. Our findings suggest that spicy food intake is predictive of AD-related cognitive decline, i.e., episodic memory; this relationship is worsened by physically inactive lifestyle.