STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human solid and blood tumors, thus suggesting that its inhibition could represent an interesting molecular target for cancer therapy. With the aim to disclose novel scaffolds for compounds active on STAT3 the potential of the 1,2,5-oxadiazole ring was explored and several new compounds substituted at positions 3 and 4 of the heterocycle were synthesized. When tested in a dual-luciferase assay, using HCT-116 cells, some compounds showed a significant inhibition value towards STAT3. So, to give support to the biological results, modeling and crystallographic studies of representative terms of the new series were performed.