Steviol is an ent-kaurene diterpenoid with interesting pharmacological activity. Several steviol derivatives with an exo-methylene cyclopentanone unit were discovered as potent antitumor agents. However, their poor selectivity for tumor cells relative to normal cells reduces their prospects as potential anticancer drugs. In this study, based on previous work, 32 steviol derivatives, including 28 new analogues, were synthesized. Their cytotoxicity against tumor cells and normal cells was evaluated. Several new derivatives, such as 7a, 7h, and 8f, with improved cytotoxic selectivity and antiproliferative activity were obtained, and the structure-activity relationship correlations were investigated. The new compound 8f displayed potent antiproliferative activity against Huh7 cells (IC50 = 2.6 μM) and very weak cytotoxicity against the corresponding normal cells HHL5 (IC50 = 97.0 μM). Further investigation showed that 8f arrested the cell cycle at the G0/G1 phase and caused reactive oxygen species overproduction, decreased mitochondrial membrane potential, and induced apoptosis of Huh7 cells through inhibition of the PI3K/Akt/mTOR and NF-κB pathway as well as upregulation of Bax/Bcl-2 ratio. The present study suggested that 8f is a promising lead compound for new cancer therapies, and the results presented herein may encourage the further modification of steviol for additional derivatives with enhanced efficacy and selectivity.