Naproxen is a nonsteroidal anti-inflammatory drug that exhibits phototoxic side effects in humans, but its mechanism of phototoxicity is ambiguous. To uncover photophysical and photochemical reaction processes of naproxen, femtosecond to nanosecond transient absorption spectroscopies were employed to directly detect excited and transient states of naproxen upon UV irradiation in pure acetonitrile, acetonitrile:water 1:1, and acetonitrile:PBS 1:1 solutions. The transient absorption data together with time-dependent density functional theory analysis-predicted absorption spectra of selected intermediates were integrated to elucidate photochemical mechanisms for reactions of naproxen in different solutions. Femtosecond transient absorption results demonstrated that naproxen has two different photochemical pathways at the early delay time before the formation of final products in various solutions. In a pure acetonitrile solvent, naproxen undergoes charge transfer to solvent to generate a radical cation intermediate, which decarboxylates to generate a radical 2B intermediate. While in an acetonitrile:PBS 1:1 solution, naproxen predominantly deprotonates first and is promoted to the singlet exited state (1NPX-), which undergoes intersystem crossing to give rise to the lowest-lying triplet states (T1). T1 then undergoes decarboxylation reaction and produces a radical 2B species. Kinetic characterization of these processes reveals that the decarboxylation reaction in an acetonitrile:PBS 1:1 solution is faster than that in a pure acetonitrile solvent. Deep studies on photophysical and photochemical processes of NPX will aid us to better understand the toxicology mechanisms associated with NPX in different conditions.