Hypoxia reportedly increases free radical generation in the body, causing oxidative stress and inhibiting β2-AR signaling. The present study correlates the prophylactic potential of quercetin and salbutamol in ameliorating fluid clearing capacity of lungs by re-sensitizing β2-AR signaling under hypoxia.Male SD rats supplemented orally with quercetin (50 mg/Kg BW), and salbutamol (2 mg/Kg BW) were exposed to hypobaric hypoxia at 7,620 m for 6 h. Western blotting and ELISA quantitated NFĸB and related genes and GPCR pathway proteins. The binding affinities of drugs with receptor were determined by SPR spectroscopy and further confirmed insilico.Quercetin and salbutamol pre-treatment significantly up-regulated the expressions of β2-AR, GPR-1, GPR-10, GCSα, cAMP content, and down-regulated GRK-2, β-arrestin, ROS, NFκB (p < 0.001), thus, enhancing alveolar fluid clearance (AFC). SPR and insilico findings revealed a higher binding affinity of β2-AR with quercetin over salbutamol.Results indicated quercetin to be a better prophylactic that augmented AFC in rats exposed to hypoxia by attenuating inflammation and stimulating β2-AR.