Prior cross-sectional studies revealed that multiple chronic conditions (MCC) and polypharmacy are associated with cognitive impairment. The purpose of this study was to determine whether the number of chronic conditions and the number of medications are associated with longitudinal changes in cognition (memory, attention/working memory, semantic ability/language, processing speed, executive function). We analyzed data from 5671 individuals (age 71.4 ± 9.3, 68 % female) from the National Alzheimer's Coordinating Center database who were cognitively unimpaired at baseline and had 3 or more subsequent visits. 57 % had more than two chronic conditions, and 44 % were taking 5 or more medications at baseline. At baseline, we observed that individuals with MCC had lower memory, attention/working memory, semantic ability/language, processing speed, and executive function performance than those without MCC. Using mixed-effect modeling approaches, we found that having a higher number of chronic conditions was associated with greater decline in semantic ability/language and executive function, and having a higher number of medications was associated with greater decline in attention/working memory, semantic ability/language, and executive function. The findings suggest that healthcare professionals and service providers should be conscious of the fact that patients dealing with MCC and those on multiple medications are vulnerable and require careful monitoring. Future studies are warranted using more comprehensive multimorbidity data and advanced analytic approaches, and prospective, controlled trials are warranted to test whether managing MCC and reducing the number of unnecessary medications or certain medications can prevent decline.