Objectives The present study set out to investigate relations of the number of chronic diseases (as a global indicator of individuals’ multimorbidity) to cognitive status and cognitive decline over six years as measured by changes in Trail Making Test (TMT) completion time in old adults and whether those relations differed by key life course markers of cognitive reserve (education, occupation, and cognitively stimulating leisure activities). Method We analyzed data from 897 participants tested on TMT parts A and B in two waves six years apart. Mean age in the first wave was 74.33 years. Participants reported information on chronic diseases, education, occupation, and cognitively stimulating leisure activities. Results Latent change score modeling testing for moderation effects revealed that a larger number of chronic diseases significantly predicted stronger increase in TMT completion time (i.e., steeper cognitive performance decline). Notably, the detrimental relation of the number of chronic diseases to stronger increase in TMT completion time (i.e., cognitive performance decline) was significantly stronger in individuals with less engagement in cognitively stimulating leisure activities in midlife. Discussion Present data suggest that disease-related cognitive decline may be steeper in individuals who have accumulated less cognitive reserve in midlife. However, greater midlife activity engagement seemed to be associated with steeper cognitive decline in any case. Implications for current cognitive reserve and neuropsychological aging research are discussed.