Purpose <p>This study aimed to explore the clinically feasible phytohypnotic(s) that mutually target sleep-promoting and wake-inhibiting corresponding brain regions during sleep, considering the preponderance of insomnia disorder and its associated fiscal burden, yet limited availability of comparatively safe hypnotics, especially to treat chronic insomnia.</p> Methods <p>Fifty-three literature-suggested phytohypnotics were screened against Food and Drug Administration (FDA)-recommended most common hypnotic drug targets: GABA(A) receptor β3 subunit/GABA_AR β3 (sleep-promoting) and Histamine 1/H1 (wake-inhibiting) receptors, using Schrödinger software (2020). Methodological rigor included phytoligand database formation, retrieving target protein structures, molecular docking of protein–ligand complexes, molecular dynamic simulations (at 50 and 100 nanoseconds/ns) of selected protein–ligand complexes, analyzing drug-likeliness, and adsorption-distribution-metabolism-excretion-toxicity (ADMET) properties of potential ligands.</p> Results <p>Quercetin, yohimbine, and rosmarinic acid were selected based on their comparatively better results in docking score, glide energy, and glide emodel for both receptors. These three further underwent molecular dynamics simulations at 50 and 100 ns, Lipinski’s drug-likeliness, and ADMET analyses. The molecular dynamics of protein–ligand complexes at 50 and 100 ns showed quercetin and yohimbine as better candidates against both receptors. In Lipinski’s drug-likeliness test, none of the three phytocompounds violated Lipinski’s rule of five (RO5). The ADMET analysis forwarded yohimbine as a clinically feasible phytohypnotic.</p> Conclusion <p>Yohimbine as a clinically practicable phytohypnotic should be considered for future strategic <i>in vitro</i> and <i>in vivo</i> experiments.</p>