The introduction of an oxime group into indirubin (INR) derivatives, including INROx, MINROx, and 6-BrINROx, and its impact on the spectral and photophysical properties of INR was investigated using a combination of fast-transient absorption (fs-TA/fs-UC) and steady-state fluorescence techniques. The oxime group introduces structural modifications that promote a rapid keto-enol tautomeric equilibrium and enhance the excited-state proton transfer (ESPT) process compared to its analogue, INR. In the oxime-indirubin derivatives investigated, the ESPT process is notably more efficient than what is observed in INR and indigo, occurring extremely fast (<1 ps) in all solvents, except for the viscous solvent glycerol. The more rapid deactivation mechanism precludes the formation of an intermediate species (syn-rotamer), as observed with INR. These findings are corroborated by time-dependent density functional theory (TDDFT) calculations. The work demonstrates that introducing an oxime group to INR, whether in nature or in the laboratory, results in an enhancement of its photostability.