Background: The complexity of drug regimens among older people tend to increase over time, as multiple medications are required to treat a single condition. Aim: This study examined the association of the drug burden index (DBI) and polypharmacy with patient health outcomes among cognitively intact older residents in aged care facilities (ACFs). Methods: A review of prescribed medications and related outcomes was conducted in a cross-sectional sample of older adults (≥60 years), recruited from 11 ACFs in Peninsular Malaysia. Frailty and quality of life (QoL) were evaluated using the Groningen frailty indicator and ‘Older People's Quality of Life – 35’ questionnaire, respectively; patients’ exposure to anticholinergic and sedative medicines was quantified using the DBI; and the mental health of residents was evaluated using the Hospital Anxiety and Depression Scale. Results: More than two-thirds of a sampled population received at least one anticholinergic or sedative medication and more than one-quarter was exposed to polypharmacy. Exposure to DBI-associated medications was noted in three of every four frail participants and was significantly correlated with frailty (r = 0.184, p = 0.023). The frail population had significantly increased risk of polypharmacy (odds ratio 6.07; 95% confidence interval 1.71–21.56; p = 0.005), but exposure to DBI-associated medications was not significantly associated with overall QoL and activity of daily living measures. Conclusion: Polypharmacy and anticholinergic and sedative burden were noticed in a substantial number of older adults in residential aged care facilities and were associated with frailty. Investing in the recruitment of pharmacists may benefit recognition of residential ACF quality of care, because pharmacy services (including pharmacists) are virtually non-existent in Malaysian residential ACFs.