Hydrangenol, a naturally occurring compound with a dihydroisocoumarin structure, exhibits various biological activities, including anti-inflammatory, anti-allergic, and antimicrobial effects at the cellular level. However, its limited pharmacokinetic profile, particularly low plasma stability, has restricted its utility as a therapeutic agent. To overcome this limitation, we employed a bioisosteric replacement strategy to improve both the stability and pharmacological efficacy of hydrangenol. For that, we designed and synthesized a series of hydrangenol derivatives bearing chromenone scaffolds, aiming to spare biological activities while enhancing plasma stability. Among the synthesized compounds, 5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one showed potent biological activities. It demonstrated a potent anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, significantly suppressing pro-inflammatory mediators such as nitric oxide and cytokines. Furthermore, on a carrageenan-induced inflammatory in vivo pain model, it exhibited strong antinociceptive effects. Notably, in vitro pharmacokinetic analysis revealed that this chromenone analog had markedly enhanced plasma stability, compared to the parent compound, suggesting its potential as a lead compound for the development of anti-inflammatory and antinociceptive therapeutics.