A total of 31 quinoline-based derivatives were designed and synthesized to develop novel anti-inflammatory drugs. After the toxicity of synthetic compounds to RAW264.7 cells were evaluated in vitro, their anti-inflammatory activity was assessed by inhibiting lipopolysaccharide (LPS)-induced NO production levels in the RAW264.7 cells. Among the derivatives, compound f4 had the best anti-inflammatory activity, which could reduce the production of pro-inflammatory cytokines NO, IL-1β, and TNF-α with corresponding IC<sub>50</sub> values of 20.40 ± 0.94, 18.98 ± 0.21 and 23.48 ± 0.46 μM. Western blot showed that f4 could inhibit the expression of LPS-induced inflammatory mediators iNOS and COX-2. Molecular docking showed that f4 could also enter the PDE4B receptor binding pocket, and the cellular thermal shift assay method indicated that the PDE4B protein bound to f4 had increased stability. Meanwhile, the inhibitory effect of this compound on the PDE4B enzyme (IC<sub>50</sub> = 0.94 ± 0.36 μM) was comparable to that of the positive drug rolipram (IC<sub>50</sub> = 1.04 ± 0.28 μM). Finally, in vivo studies showed that f4 could improve the degree of foot swelling and knee joint pathology in adjuvant-induced arthritic rats and decrease the levels of serum inflammatory factors TNF-α and IL-1β in a dose-dependent manner. Therefore, the development and design of quinoline-based derivatives for anti-inflammatory applications could be considered opportunities and challenges.