Despite selective COX-2 inhibitors existing, they do not fully meet the demand for safer anti-inflammatory drugs. COX-2 and 15-LOX dual inhibition offers a promising avenue for developing safer NSAIDs and may play a crucial role in the fight against cancer. Thus, we designed and synthesized new 1,3,5-triaryl pyrazolines as dual COX-2/ 15-LOX inhibitors with potent anticancer activity. The synthesized compounds were evaluated in vitro as dual COXs/15-LOX inhibitors and for anticancer activity against human colorectal cancer cell lines HT-29 and HCT116. The pyrazolines 4a, 4c, 5h, and 5i exhibited outstanding inhibition of the COX-2 isoenzyme (IC 0.013 - 0.022 μ M), demonstrating potency equal to or surpassing celecoxib (IC 50 = 0.019 50 μ = M). Notably, com pounds 4a and 4c exhibited COX-2 selectivity indices (SI = 1256.74 and 804.78, respectively), far surpassing celecoxib (SI = 178.79). Additionally, they showed potent 15-LOX inhibitory activities (IC 50 respectively), outperforming NDGA (IC 50 =5.29 μ =1.19 and 2.80 μ M, M). Also, the in vivo results indicated that compounds 4a and 4c exhibit non-ulcerogenic performance. Thus, they emerged as the most promising candidates for dual-selective inhibition of COX-2 and 15-LOX. Compound 5i demonstrated superior COX-2 inhibitory potency (IC 50 μ M) along with substantial anticancer activity against the HT-29 and HCT116 cell lines (IC 50 = 0.018 =11.46 and 18.09 μ M, respectively). This indicates that 5i could be a promising lead for the design of a potent anti-inflammatory candidate and provide a safer approach to cancer prevention, particularly for colon cancer. Molecular modeling has simulated potential binding interactions of our synthesized pyrazolines within the active sites of COX-2 and 15-LOX, and the MD simulations throughout 100 ns demonstrated stable binding complexes.