Novel coumarin-piperazine-2(5H)-furanone hybrids 5a–l were efficiently synthesized by introducing a furanone scaffold into coumarin using piperazine as a linker. The cytotoxicity of all hybrids 5a–l were evaluated by MTT assay on human lung cancer A549 cells and normal human lung fibroblast WI-38 cells with cytarabine (CAR) as a positive control. Hybrid 5l (IC50 = 11.28 μM) was the most toxic to A549 cells, 18-fold more toxic than the reference CAR (IC50 = 202.57 μM). Moreover, hybrid 5l (IC50 = 411.93 μM) was less toxic to WI-38 cells, with a much higher selectivity (5l, SI ≈ 37, WI-38/A549) than CAR (SI ≈ 2). Structure–activity relationship analysis showed that both the cytotoxicity against A549 cells and selectivity (WI-38/A549) were greatly improved when the bornyl group was incorporated in the hybrids (5c, 5f, 5i and 5l). Further, hybrid 5l was more toxic and selective against four types of human lung cancer cells (A549, Calu-1, PC-9 and H460; IC50 = 5.72–45.46 μM; SI ≈ 9–72) than three other types of human cancer cells (SK-BR-3, 786-O and SK-OV-3, IC50 = 39.07–130.82 μM; SI ≈ 0–2), showing remarkable specificity. In particular, hybrid 5l (IC50 = 5.72 μM) showed the highest cytotoxicity against H460 cells with the highest selectivity of up to 72 (WI-38/H460). Flow cytometric analysis showed that hybrid 5l induced apoptosis in H460 cells in a concentration-dependent manner. Molecular docking studies revealed a high binding affinity of hybrid 5l with CDK2 protein. Hybrid 5l is expected to be a leading candidate for anti-lung cancer agents.