<p>Photodynamic therapy (PDT) is a promising non-invasive tumor treatment, whose efficacy relies critically on the photophysical and photochemical properties of photosensitizers. Traditional photosensitizers usually suffer from aggregation-caused quenching (ACQ), while D-π-A type aggregation-induced emission (AIE) photosensitizers can overcome this drawback by inhibiting intermolecular π-π stacking. Current studies mainly focus on tuning π-bridges and acceptors, yet the systematic regulation mechanism of donor structure remains insufficiently understood, especially for systems with a fixed thiophene π-bridge and 1,2-bis(cyanomethylene)indane acceptor. Herein, eight D-π-A AIE photosensitizers with different donors were investigated by DFT and TD-DFT to reveal the regulation rules of donor engineering. All molecules displayed typical AIE conformations with local coplanarity and overall torsion. Donor engineering precisely adjusted molecular dipole moments and electrostatic potential distributions; electron-rich heterocyclic donors and methoxy-substituted triphenylamine significantly promoted intramolecular charge transfer (ICT). Phenoxazine and dimethoxy-substituted triphenylamine showed the smallest HOMO–LUMO gap (<i>ΔEg</i> ≈ 1.94&#xa0;eV), further facilitating ICT. Phenothiazine exhibited the best intersystem crossing (ISC) performance with the largest spin–orbit coupling (ξ(S₁T₃) = 0.889&#xa0;cm⁻¹) and lowest energy barrier, thus giving the highest triplet yield potential. By contrast, tetraphenylethylene showed the lowest ISC efficiency due to weak SOC. This work clarifies the multi-level regulation mechanism of donor units and establishes clear structure–property relationships. It provides a rational theoretical strategy for designing high-performance AIE photosensitizers and supports their further synthesis, biological evaluation, and translational applications in PDT and biomedical fields.</p>