We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a, identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target compounds 1b, 1g-h, 1af and 1ah (IC = 3.10-6.93 μM) had good in vitro activity against RSV, which were better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity (CC: 2490.33 μM) and the highest selective index (SI = 673.06), suggesting its promising potential as a candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai (ICs: 1.87-14.28 μM) were more active against IAV than or comparable to ribavirin (IC: 15.36 ± 0.93 μM). Particularly, the most active compound 1ae (IC: 1.87 ± 0.58 μM) was found to be 8.2-fold more potent than the reference drug, which could inhibit the virus transcription and replication cycle at an early stage.