In photopharmacology, molecular photoswitches enable light-controlled drug activities, offering precision in targeting biomolecular functions while minimizing side effects. Photostatins (PSTs) are photoswitchable analogs of combretastatin A-4 (CA4), designed to inhibit tubulin polymerization for cancer treatment. However, the influence of substituents and molecular environments on their photochemistry remains unclear. In this work, the cis-to-trans photodynamics of five PSTs (PST1 to PST5) in the vacuum and aqueous solution were simulated using the ab initio multiple spawning (AIMS) coupled with correlated multireference electronic structure calculations. Four distinct minima in the same conical intersection seam were discovered, serving as nonradiative decay channels. The aqueous environment slows photoisomerization and lowers its quantum yields and changes the structures near the conical intersection seam. Substituent position and electronegativity significantly impact the isomerization kinetics by altering energy gaps between MECIs and the S