<p>Hypertension, diabetes, and hyperlipidemia are common in Singapore and linked to cognitive decline. Evidence on cognitive effects of related medications is mixed, with limited multiethnic Singapore data. This study investigated associations between antihypertensive, antidiabetic, and antihyperlipidemic medications and cognitive performance. This cross-sectional (<i>n</i> = 1556) and longitudinal study (<i>n</i> = 565) utilized two datasets from a multiethnic Asian population. Medications were categorized by Anatomical Therapeutic Chemical (ATC) Classification, and analyses compared users and non-users across the full sample and within respective medical conditions. Cognitive function was assessed using a neuropsychological battery evaluating seven domains and global cognition. Linear regression and linear mixed models were used for cross-sectional and longitudinal analyses, respectively. Cross-sectional findings showed no association between antihypertensive or antihyperlipidemic use and cognition. Among diabetic patients, antidiabetic use was linked to poorer global cognition (<i>β</i> = −0.149 (−0.253, −0.045)), executive function (<i>β</i> = −0.287 (−0.468, −0.093)), and visual memory (<i>β</i> = −0.217 (−0.343, −0.092)). Longitudinally, antihypertensive use was associated with better global cognition (<i>β</i> = 0.239 (0.052, 0.426)) and visual memory (<i>β</i> = 0.316 (0.11, 0.522)) among hypertensive participants, while antidiabetic use was associated with poorer visuoconstruction (<i>β</i> = −0.514 (−0.87, −0.158)), and antihyperlipidemic use was not associated with cognition. Baseline antihypertensive use may be associated with better cognitive performance among hypertensive individuals. Poorer cognition among antidiabetic users may reflect underlying disease severity rather than drug toxicity, given the limited longitudinal evidence of consistently poorer cognitive performance. No associations were observed with antihyperlipidemic use. Further large longitudinal studies are needed.</p>