Capsaicin (CAP) is an alkaloid isolated from pepper fruit, which possesses various pharmacological activities including antioxidant, anti-inflammatory, antibacterial and gastric mucosa protection. However, its inherent poor aqueous solubility and strong irritation impede the further clinical application. In our study, acyclic cucurbit[n]urils (ACBs, M1, M2 and M3) were rationally utilized to prepare a series of CAP inclusion complexes to improve the bioavailability and reduce stimulation. Their properties and inclusion behaviors were further investigated by multiple characterization methods, the data indicated that the inclusion complexes of ACBs/CAP were formed by a stoichiometric ratio of 2:1 with strong binding interaction. After complexation, the solubility of CAP was significantly increased by 12,076 times and its antioxidant activity also increased. Moreover, the anti-inflammatory activity and the ability to prevent gastric mucosal injury were both significantly improved, and the inhibition rate of nitric oxide (NO) and interleukin-1β (IL-1β) has been effectively improved while cytotoxicity against human normal hepatocytes cell (LO2), human lung fibroblasts cell (HLF) and the human gastric mucosal cell (GES-1) was greatly attenuated. Confocal laser scanning microscope (CLSM) images indicated that the complexes could be efficiently internalized by GES-1 cells and primarily located in cytoplasm. In vivo model of mouse, our complexes exhibited excellent biosafety. In summary, our study may provide a promising new strategy for the further clinical application of CAP.