Lipoxygenase (LOX) and cyclooxygenase (COX) pathways generate biologically active mediators implicated in inflammatory disorders and several classes of cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the COX pathway by inhibiting the COX-1 and COX-2 enzymes. We reported earlier that several NSAIDs, including naproxen, aspirin and acetaminophen, inhibited lipoxygenase (LOX) enzyme at sub-micromolar concentrations. In continuation, the present work demonstrates the anti-LOX activity of nine more NSAIDs supported by in vitro, in silico, MD simulation and breast cancer cell line studies. All tested drugs displayed potent to excellent inhibitory profiles with IC50 values <24.93 ± 0.64 μM. Aceclofenac (IC50 0.85 ± 0.06 μM) was the most active drug, followed by indomethacin (IC50 1.13 ± 0.07 μM), meloxicam (IC50 1.94 ± 0.07 μM) and ketorolac (IC50 9.26 ± 0.82 μM). Celecoxib (IC50 15.81 ± 0.71 μM), lornoxicam (IC50 16.54 ± 0.28 μM) and nimesulide (IC50 19.87 ± 0.85 μM) showed excellent inhibitory profiles. Flurbiprofen (IC50 21.73 ± 0.93 μM) and etoricoxib (IC50 24.93 ± 0.64 μM) moderately inhibited the target enzyme. SAR studies revealed that active molecules decorated with the carboxylate group afforded strong binding interactions as observed by in vitro assays and structural features. Other drugs, including enol derivatives and celecoxib, also showcased enhanced binding interactions. However, the cytotoxic effects of NSAIDs against the MCF-7 breast cancer cell line did not disclose significant anticancer activity. Molecular docking studies against human 5-LOX offered the best binding affinities for aceclofenac (-13.54 kcal/mol), accompanied by conventional hydrogen bonding and hydrophobic interactions as supported by the in vitro results. Docking studies with DNA dodecamer established minor groove binding with their possible role in DNA replication and gene expression. Density functional theory (DFT) and ESP studies, MD simulations and MMPBSA free energy calculations further reiterated the stability of ligand-receptor complexes. Overall, these findings highlight the potential of targeted NSAIDs as dual COX/LOX inhibitors with broader therapeutic relevance in inflammatory disorders.