In this work we strive to unravel the relationships between the two‐photon absorption (2PA) cross‐sections and structural modifications in an extended panel (280 compounds) of large difluoroborate dyes. More specifically, we use theoretical tools based on Time‐Dependent Density Functional Theory (TD‐DFT), to predict the one and two‐photon absorption properties of all compounds. The BF2‐carrying dyes usually posses a great interest for 2PA bioapplications as smartly designed BF2‐derivatives show good photophysical properties and high quantum yields in aqueous medium. For practical applications, it is important to maximize their 2PA response as well as absorption wavelength. This is why we explore here various strategies for maximizing the 2PA cross‐section: core modifications, multi‐branching, variation of the nature and length of the π‐conjugated linkers, addition of various donor and acceptor substituents. Our results suggest that large values of 2PA cross‐section and redshifted absorption wavelength can be achieved for all studied cores by using the vinylene‐type linkers and asymmetrical substitution with at least one strong peripheral donor group.