The benzo furan-extended 2-(2'-hydroxybenzofuranyl) benzazole derivants (HBBX) have attracted widespread attention for their excellent photophysical properties. Some subtle structural alterations have been proven to influence the spectral characteristics significantly. However, a comprehensive understanding of the influence of structural regulation is still lacking. Here, the effects of heteroatoms and substituent groups on the excited state intramolecular proton transfer (ESIPT) process and photophysical properties of HBBX derivants are investigated by the density functional theory/time-dependent density functional theory (DFT/TDDFT). Our simulation results show that heteroatoms and substituent groups significantly change the hydrogen bond strength of HBBX derivants. To the heteroatoms, the HBBX substituted by the N atom (HBBI) has the lowest ESIPT energy barrier in the first excited state, and the substitution of tBu group (HBBO-1) can cause the maximum energy barrier reduction to the substituent groups. Moreover, the absorption, emission spectra and hole-electron analysis are consistent with the experimental results, and the simulation results show that HBBI has the lowest degree of intramolecular charge transfer and highest fluorescence intensity in all HBBX derivants. Our work will provide the comprehensive insight into the effects of heteroatoms and substituent groups on ESIPT processes and photophysical properties for the design of fluorescent materials.