Abstract: The drying is an important part of the processing of Ziziphi Spinosae Semen (ZSS) in the producing area and has an important effect on the quality of ZSS. In this study, an integrated ¹H nuclear magnetic resonance and gas chromatography-mass spectrometry method was developed to reveal the effects of vacuum drying (VD), freeze-drying (FD), and hot air drying (HAD) method on the chemical composition and antioxidant activity of ZSS. Then the effects of different drying methods on the quality of ZSS were investigated. The results showed that the VD produced high contents of 6 fatty acids (palmitic acid, linoleic acid, oleinic acid, stearic acid, squalene, and γ-tocopherol), 7 amino acids (leucine, isoleucine, valine, alanine, γ-aminobutyric acid, glutamine, and threonine), and 2 carbohydrates (α-glucose and β-glucose), but exhibited weak DPPH radical scavenging activity, ABTS cation radical scavenging activity and FRAP antioxidant activity (FD>VD>HAD). However, FD gave an improved secondary metabolite profile retention, such as jujuboside A, betulinic acid, magnoflorine, and 6ʹʹʹ-feruloylspinosin, thereby resulting in a superior DPPH radical scavenging activity (IC₅₀: 2.82±0.15 mg/mL), ABTS cation radical scavenging activity (IC₅₀: 0.86±0.02 mg/mL) and FRAP antioxidant activity (58.91±2.87 mg V_C/g). Thus, FD was a suitable drying method to maximize the product quality retention of ZSS. This study can provide a scientific reference for the establishment of reasonable processing technical specifications of ZSS and provide an experimental basis for improving the quality of ZSS.