High fructose and cholesterol diets (HFCDs) cause hypercholesterolemia, hypertriglyceridemia, and many acute and chronic serious diseases. Current established treatments, such as simvastatin (SIM) and gemfibrozil (GEM), have been successful in lowering cholesterol and triglyceride levels, but their long-term use poses a risk for organ dysfunction. Herbal medicine addition to this treatment can improve patient outcomes. This study examined the effects of Acalypha indica L. (AI) root extract in improving the efficacy of SIM and GEM treatment and attempted to reduce their side effects. Five of the seven male Sprague-Dawley rat groups were maintained daily on HFCD for 4 weeks while being treated with either SIM, GEM, AI, SIM+AI, or GEM+AI. The remaining two groups were given only HFCD and normal diet, respectively. Liver HMG-CoA reductase and PPAR-α, blood total cholesterol and triglyceride levels, and liver histopathology were measured after a 1-month therapy. The SIM+AI group had low HMG-CoA reductase levels, whereas the GEM+AI group had high PPAR-α levels. The GEM+AI group showed normal liver histopathology, whereas the SIM+AI and HFCD-only groups showed similar features. Adding AI to SIM and GEM lowered triglyceride levels. GEM+AI significantly lowered cholesterol levels, indicating that AI functions synergistically as a PPAR-α agonist. © 2019 Journal of International Dental and Medical Research.