Introduction: Inhibiting cyclooxygenase-2 (COX-2) is a potential strategy in inflammation therapy. Thus, developing COX-2 inhibitors plays a pivotal role in efficient inflammation treatment. This study discloses the synthesis of new heterocyclic compounds incorporating pyridine, pyran, and/or pyrazole moieties as COX-2 inhibitors. Methods: In this study, the Claisen–Schmidt reaction of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)ethan-1-one 1 and p-methoxybenzaldehyde in ethanol containing aqueous sodium hydroxide (10%) led to the formation of 1-(5-hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)-3-(4-methoxyphenyl)prop-2-en-1-one) 2. The latter compound was allowed to react as a key precursor with various nucleophiles such as ethyl cyanoacetate, malononitrile, cyclohexanone, ethyl acetoacetate, hydrazine, cyano acid hydrazide, hydrazide, and/or thiosemicarbazide to yield new heterocyclic derivatives comprising pyridine, pyran, and/or pyrazole moieties 3–15, according to the Michael addition reaction. The newly synthesized compounds were depicted using spectroscopic techniques such as IR, ¹H-NMR, ¹³C-NMR, and MS. Moreover, their anti-inflammatory efficiency was in vitro evaluated by means of protein denaturation inhibition and cell membrane protection assay. Results: The results of 2^−ΔΔct values of COX-2 expression for compounds 6, 11, 12, and 13 were 6.6, 2.9, 25.8, and 10.1, respectively. Therefore, compound 12, followed by 13, 11, and 6, showed potent anti-inflammatory properties by in vitro evaluation. Further, an in silico molecular docking study was performed on the best-docked compounds and reference drug (Diclofenac) to investigate their binding affinities against the active site of the target enzyme. The obtained results from the in silico study aligned with the biological evaluation. Conclusions: The studies open new doors for designing new heterocycles containing pyridine, pyran, and/or pyrazole moieties as potent anti-inflammatory agents.