Farnesyl pyrophosphate synthase (FPPS) is one of the enzymes in the cholesterol synthesis pathway. The important roles that FPPS plays in the body has led to the growing interest in developing FPPS inhibitors for anti-cancer therapies. Nitrogenous bisphosphonates are FPPS inhibitors and have been used for the treatment of skeletal conditions. However, they have limited systemic absorption, limiting their use as anti-cancer agents. The aim of this study is to design and develop novel FPPS inhibitors with more suitable physiochemical properties. We constructed a pharmacophore model based on the interactions of zoledronate (ZOL) and FPPS which we used for screening. Hits were subjected to docking to filter candidates with best binding characteristics. We identified 8 candidates to proceed to in vitro studies to determine their anti-cancer activity. We also synthesized a series of compounds based on structure-activity relationship studies of FPPS to explore the relationship between the changes in chemical structure and anti-cancer activity. Cell viability assay identified 5 candidates (36b, d, f-h) that inhibit Huh7 cell viability at 25 µM. They exhibited stronger cell viability inhibition than ZOL, with IC50 values at low micromolar range. Lipidomic analysis and the use of cholesterol-binding probe (D4H) showed that 36b can reduce the increase in cellular cholesterol concentration significantly after pre-treatment with MβCD. 36b was found to activate apoptosis via inducing ER stress and activation of unfolded protein response using immunoblotting. In particular, 36g and 36h, work synergistically with paclitaxel, suggesting its potential use as combination therapy. Overall, this family of compounds can reduce cellular cholesterol concentration and exert anti-cancer activity. Further studies are required to fully understand the mechanism of action of these compounds.