The Yes-associated protein-1 (YAP1) is an essential regulator of human Hippo signaling pathway and functions through interaction with TEA domain-4 (TEAD4) transcription factor involved in the tumorigenesis of nasopharyngeal cancer. Previously, a parallel helix-helix interaction (PHHI) was identified as the key hotspot at YAP1-TEAD4 complex interface and has been exploited as an attractive druggable target to disrupt the complex. In this study, we investigated a roughly orthogonal cation-π-π stacking system across the crystal PHHI packing interface by integrating computational modeling and binding assay, which forms between one YAP1 helical residue Phe69 and two TEAD4 helical residues Phe373/Lys376. A synergistic effect between cation-π and π-π interactions was observed; they separately represent two wings of the stacking system. The π-electron is primarily responsible for the synergistic effect. Combination between diverse aromatic/charged amino acids. as well as neutral alanine on the cation-π-π stacking, revealed that the presence of aromatic tryptophan and charged arginine at, respectively, the residues 373 and 376 of TEAD4 helix can considerably improve PHHI binding affinity by ~6-fold, whereas neutral alanine substitution on each residue and on both would reduce the affinity significantly, confirming a strong synergistic effect involved in the roughly orthogonal cation-π-π stacking system at YAP1-TEAD4 PHHI interface.