This study investigated the influences of drying method (oven-, freeze-, and shade-drying) and extraction solvent (ethanol and water) on the bioactivities of Cirsium setidens. Antioxidant activity was evaluated by DPPH radical scavenging ability, anti-diabetic activity was determined by the inhibitory activity of two enzymes: α-glucosidase and α-amylase, while anti-proliferation activity was assessed by MTT assay of three human cancer cell lines (KB, A549, and PC-3). Results indicated that bioactivities were extremely affected by solvent; water extracts contained more phenolics, exhibited strong anti-diabetic effect, but no activity of anti-proliferation, while the ethanolic extracts rich in flavonoids showed profound DPPH radical scavenging and anti-proliferation ability, yet low activity of antidiabetes. Among the drying methods, freeze-drying extracts preserved more flavonoids and exhibited better activity of anti-proliferation, while shade-drying extracts contained higher phenolics and showed stronger activity on antidiabetes, oven-drying gave the lowest content of phenolics. Hence, antioxidant and anti-diabetic effects were positively related to phenolic content, meanwhile an extremely significant correlation coefficient had been found between anti-proliferation activity and flavonoid content, it can be concluded that drying method and extraction solvent affect bioactivities by phenolic and flavonoid contents.