In order to improve the potential of celastrol against non-small-cell lung cancer cells, the privileged structure, thiazolidinedione, was introduced into its C-20 carboxylic group with acetylpiperazine as a linker, and the thiazolidinedione-conjugated compounds <b>10a</b>-<b>10t</b> were prepared. The target compounds were evaluated for their cytotoxic activities against the A549 cell line, and the results showed that most of the compounds <b>10a</b>-<b>10t</b> displayed improved potency over celastrol, and compound <b>10b</b> exhibited significant activity against the A549 cell line, with an IC<sub>50</sub> value of 0.08 μM, which was 13.8-fold more potent than celastrol (IC<sub>50</sub> = 1.10 μM). The mechanistic studies suggested that <b>10b</b> could induce A549 cell apoptosis, as evidenced by Hoechst 33342 staining and annexin V-FITC/propidium iodide dual staining assays. Western blot analysis suggested that compound <b>10b</b> could upregulate Bax expression, downregulate Bcl-2 expression, and activate the mitochondria-mediated apoptotic pathway. Furthermore, compound <b>10b</b> could effectively inhibit tumor growth when tested in an A549 cell xenograft mouse model. Collectively, compound <b>10b</b> is worthy of further investigation to support the discovery of effective agents against non-small-cell lung cancer.