In this study, a series of 3,6-disubstituted-1,2, 4-triazolo-[3,4-b]-1,3,4-thiadiazoles (5a–t) were synthesized by condensing 4-amino-3-mercapto-(4H)-1,2,4-triazoles (4a–c) with different aromatic or aroyl acids through one-pot reaction. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation actions. Some of the newly synthesized compounds showed very good anti-inflammatory activity with low GI toxicity and reduced lipid peroxidation. These compounds also showed interesting profile of analgesic activity in acetic acid-induced writhing test. The findings of the study indicate that the synthesized compounds have superior GI safety profile along with reduction in lipid peroxidation as compared to that of the standard.