The potential of natural phytochemicals in mitigating depression has been supported by substantial evidence. This study evaluated a total of 88 natural phytochemicals with potential antidepressant properties by targeting serotonin (5-HT) receptors (5-HT1A, 5-HT4, and 5-HT7) using molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis, internal coordinates normal mode analysis (NMA), molecular dynamics simulation (MDS), and free energy calculation. Five evaluated compounds (Genistein, Kaempferol, Daidzein, Peonidin, and glycitein) exhibited favorable pharmacokinetic properties and improved binding scores, indicating their potential as effective antidepressants. Redocking and superimposition analysis of 5-HT with cocrystal structures validated these findings. Furthermore, NMA, MDS, and free energy calculations confirmed the stability and deformability of the ligand-receptor complexes, suggesting that these phytochemicals can effectively interact with 5-HT receptors to modulate depressive symptoms. These powerful phytochemicals, abundantly found in soybeans, fruits, vegetables, and herbs, represent a promising avenue for developing natural treatments for depression. Further in vitro and in vivo studies are warranted to explore their efficacy in alleviating stress and depression through their interactions with 5-HT receptors.