This article briefs about the efforts taken to synthesis, characterize and develop (E)-5-methyl-2-phenyl-3-(thiophen-2-yl)-7-(thiophen-2-ylmethylene)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridine and their analogs. In the two-step reaction, the first step is the synthesis of (3Z,5E)-1-methyl-3,5-bis(thiophen-2-ylmethylene)piperidin-4-one derivatives (3a-l) by stirring the mixture of 1-methylpiperidin-4-one and substituted thiophene-carbaldehydes in presence of methanol. In the second and final step, compounds 3a-l were refluxed with phenyl-hydrazine to achieve the target compounds (E)-5-methyl-2-phenyl-3-(thiophen-2-yl)-7-(thiophen-2-ylmethylene)-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridine and their analogs (5a-l) in good yield. These compounds were used to assess their inflammation regulation properties in macrophages by executing quantitative pro-inflammatory and anti-inflammatory proteins such as TNF-α, IL-1β, IL6, and IL-10 respectively. In silico and in vitro COX-2 inhibition studies helped to understand the molecular interaction or plausible mechanism during the inflammation regulation that showed by the compounds. In the results, among the 12-member family of pyrazolo-pyridines (5a-l), 5a, 5b, 5g, and 5j were showed excellent in silico binding affinity (1–10 nM), least binding energy (−12.45 to −14.27 kcal/mol) and in vitro COX-2 inhibition (relative percentage activity maximum 96.42%). Thus, these compounds perhaps to be future anti-inflammatory drugs.