In search of strategies to operate photochromic compounds in aqueous environments, we synthesized two oxazines with a pendant oligo(ethylene glycol) chain each and a co-polymer with multiple oxazine and oligo(ethylene glycol) tails appended to a common macromolecular backbone. The hydrophilic character of the oligo(ethylene glycol) chains imposes solubility in water on two of the three systems. Their laser excitation in water opens the oxazine ring in less than 6 ns to generate zwitterionic isomers able to absorb in the visible region of the electromagnetic spectrum. The photogenerated species revert spontaneously back to the original forms with first-order kinetics. The transition from organic solvents to aqueous environments, however, causes a five-fold decrease in the quantum yield of the photoinduced ring-opening process and elongates the lifetime of the photogenerated isomer from the nanosecond to the microsecond domain. These hydrophilic and photochromic switches can be interconverted hundreds of times between their two states with no sign of degradation in water. As a result, our structural design for the realization of water-soluble photochromic compounds can lead to the development of viable strategies to modulate the structures and functions of biomolecules with microsecond switching times and excellent fatigue resistances under the influence of optical stimulation.