In the SImplification of Medications Prescribed to Long-tErm care Residents (SIMPLER) cluster-randomized controlled trial, we evaluated the impact of structured medication regimen simplification on medication administration times, falls, hospitalization, and mortality at 8 residential aged care facilities (RACFs) at 12 month follow up. In total, 242 residents taking ≥1 medication regularly were included. Opportunities for simplification among participants at 4 RACFs were identified using the validated Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE). Simplification was possible for 62 of 99 residents in the intervention arm. Significant reductions in the mean number of daily medication administration times were observed at 8 months (−0.38, 95% confidence intervals (CI) −0.69 to −0.07) and 12 months (−0.47, 95%CI −0.84 to −0.09) in the intervention compared to the comparison arm. A higher incidence of falls was observed in the intervention arm (incidence rate ratio (IRR) 2.20, 95%CI 1.33 to 3.63) over 12-months, which was primarily driven by a high falls rate in one intervention RACF and a simultaneous decrease in comparison RACFs. No significant differences in hospitalizations (IRR 1.78, 95%CI 0.57–5.53) or mortality (relative risk 0.81, 95%CI 0.48–1.38) over 12 months were observed. Medication simplification achieves sustained reductions in medication administration times and should be implemented using a structured resident-centered approach that incorporates clinical judgement.