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Abstract Upon blue‐light absorption, LOV domains efficiently undergo intersystem crossing (ISC) to the triplet state. Several factors potentially contribute to this efficiency. One often proposed in the literature is the heavy atom effect of the nearby (and eventually adduct‐forming) cysteine. However, some LOV domain derivatives that lack the cysteine residue also undergo ISC efficiently. Using hybrid multireference quantum mechanical/molecular mechanical (QM / MM) models, we investigated the effect of the electrostatic environment in a prototypal LOV domain,Arabidopsis thalianaPhototropin 1 LOV2 (AtLOV2), compared to the effect of the dielectric of an aqueous solution. We find that the electrostatic environment of AtLOV2 is especially well tuned to stabilize a triplet state, which we posit is the state involved in the ISC step. Other low‐lying triplet states that have and character are ruled out on the basis of energetics and/or their orbital character. The mechanistic picture that emerges from the calculations is one that involves the ISC of photoexcited flavin to a triplet state followed by rapid internal conversion to a triplet state, which is the state detected spectroscopically. This insight into the ISC mechanism can provide guidelines for tuning flavin's photophysics through mutations that alter the protein electrostatic environment and potentially helps to explain why ISC (and subsequent flavin photochemistry) does not occur readily in many classes of flavin‐binding enzymes.