Gastric cancer (GC) is a common malignant disease worldwide, and finding novel agents and strategies for the treatment of GC are of urgent need. Celastrol (CEL) is a well-known natural product with antineoplastic activity. In this study, pyrazole analogues were introduced at the C-29 position of CEL. A total of 24 new derivatives were designed, synthesized, and evaluated for their mechanism and antitumor activity in vitro and in vivo. Among them, compound 21 exhibited the best activity against BGC-823 cells (IC50 = 0.21 ± 0.01 μM). Further biological studies showed that 21 significantly raised the reactive oxygen species (ROS) levels to activate the apoptotic pathway, causing mitochondrial dysfunction in BGC-823 cells. In addition, 21 also arrested cells in the G2/M phase to induce tumor cell apoptosis. In a nude mouse tumor xenograft model, 21 exhibited a better tumor inhibition rate (89.85%) than CEL (inhibition rate 76.52%). Taken together, the present study has provided an anticancer lead compound candidate, 21, and has revealed that increased ROS generation may be an effective strategy in the treatment of GC.