Emerging evidence points to the intertwining framework of inflammation and oxidative stress in various ailments. We speculate on the potential impact of the magic shotgun approach in these ailments as an attempt to mitigate the drawbacks of current NSAIDs. Hence, we rationally designed and synthesized new tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine monomers/heterodimer as dual selective COX-2/15-LOX inhibitors with potent antioxidant activity. The synthesized compounds were challenged with diverse in vitro biological assays. Regarding the monomeric series, compound 5k exerted the highest COX-2 inhibitory activity (IC(50) = 0.068 μM, SI = 160.441), while compound 5i showed the highest 15-LOX inhibitory activity (IC(50) = 1.97 μM). Surpassing the most active monomeric members, the heterodimer 11 stemmed as the most potent and selective one in the whole study (COX-2 IC(50) = 0.065 μM, SI = 173.846, 15-LOX IC(50) = 1.86 μM). Heterodimer design was inspired by the cross-talk between the partner monomers of the COX-2 isoform. Moreover, some of our synthesized compounds could significantly reverse the LPS-enhanced production of ROS and proinflammatory cytokines (IL-6, TNF-α, and NO) in RAW 264.7 macrophages. Again, the heterodimer showed the strongest suppressor activity against ROS (IC(50) = 18.79 μM) and IL-6 (IC(50) = 4.15 μM) production outperforming the two references, celecoxib and diclofenac. Regarding NO suppressor activity, compound 5j (IC(50) = 18.62 μM) surpassed the two references. Only compound 5a significantly suppressed TNF-α production (IC(50) = 19.68 μM). Finally, molecular modeling simulated the possible binding scenarios of our synthesized thienopyrimidines within the active sites of COX-2 and 15-LOX. These findings suggest that those novel thienopyrimidines are promising leads showing pharmacodynamics synergy against the selected targets.