In continuation of efforts to identify better anti-inflammatory agents, the present work aimed to functionalize the 3rd position of 1,2-benzothiazine 1,1-dioxide with a 1,2,3 triazole moiety. A series of novel 1-substituted-triazole linked 1,2-benzothiazine 1,1-dioxido propenone derivatives 8a–s & 12a–l were prepared from 1-substituted 1,2,3-triazol-4-aldehydes 6 & 11 with N-methyl-3-acetyl-4 hydroxybenzothiazine-1,1-dioxide 7 by condensation. Final compounds 8 and 12 were evaluated for their anti-inflammatory activity and ability to inhibit monocyte-to-macrophage transformation, a process pivotal during the development and progression of atherosclerosis. Among all the compounds, 12e, 12g, 12i, 12j, 12k and 12l showed impressive anti-inflammatory activity against TNF-α, IL-1β and MCP-1 cytokines released in a dose-dependent manner. The most promising compounds 12g, 12i and 12l further significantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 activity and PMA-induced monocyte-to-macrophage differentiation, thereby suggesting their potential to serve not only as new anti-inflammatory agents, but also as novel molecules affecting monocyte-to-macrophage differentiation.