The labdane diterpene hedychenone, isolated from <i>Hedychium spicatum</i>, is an example of a furan-containing natural product. Herein, a new and efficient method for the synthesis of 19 new thio analogues of hedychenone is reported. The present methodology exhibits a broad substrate scope with good to excellent yields without metal or base under mild reaction conditions. The natural compound <b>1</b> and four semisynthetic derivatives (<b>3a</b>, <b>3b</b>, <b>3i</b>, and <b>3j</b>) exhibited strong α-glucosidase inhibition activity with IC<sub>50</sub> values of 15.93 ± 0.29, 9.70 ± 0.33, 11.82 ± 0.06, 12.23 ± 0.33, and 12.15 ± 0.14 μg/mL, respectively. In addition, compound <b>3e</b> (6.0 ± 0.04 mm; zone of inhibition) displayed antibacterial activity against <i>Staphylococcus aureus</i>. This study increases the chemical diversity of bioactive hedychenone derivatives and provides a direction for the development of antidiabetic agents.