Aging is significantly associated with the development of comorbid chronic conditions. These conditions indicate the use of multiple medications, and are often warranted by clinical guidelines. The aim of the present study was to evaluate medication appropriateness and frailty among Malaysian aged care home residents with chronic disease. The participants were 202 elderly (≥65 years) individuals, a cross-sectional sample from 17 aged care homes. After ethics approval, each participant was interviewed to collect data on sociodemographics, frailty status (Groningen Frailty Indicator [GFI]), medication appropriateness (Medication Appropriateness Index (MAI), the 2015 Beers’ criteria (Potentially Inappropriate Medication [PIM]), and 2014 STOPP criteria (Potentially Inappropriate Prescribing [PIP]). The findings show that 81% (n = 164) and 42% (n = 85) were taking medications for cardiovascular and central nervous system-related conditions, respectively, and 34% were using medications for diabetes (n = 69). Each participant had a mean of 2.9 ± 1.5 chronic diseases, with an average GFI score of 6.4 ± 3.6. More than three-quarters of the participants (76%) were frail and polypharmacy was a factor in nearly half (48%); 41% and 36% were prescribed at least one PIP and PIM, respectively, whereas the average MAI score was 0.6 (range: 0–6). The number of medications used per participant correlated significantly and positively (0.21, P = .002) with GFI score. These findings reinforce the need for participants of aged care homes to receive periodic medication review aimed at minimizing morbidity associated with inappropriate pharmacotherapy.