Dissolved organic matter (DOM) plays an important role in carbon cycling within inland surface waters. Under sunlight irradiation, DOM undergoes complete photooxidation to produce carbon dioxide (CO2) and partial photooxidation that alters the molecular composition of DOM. However, a mechanistic understanding of the relationship between DOM composition and its susceptibility to partial and complete photooxidation in surface waters is currently lacking. This work combines light exposure experiments with high-resolution mass spectrometry to investigate DOM photooxidation using two DOM isolates and DOM from 16 lakes that vary in trophic status and size. High ratios of oxygen consumption to dissolved inorganic carbon (DIC) production demonstrate that all samples undergo extensive partial photooxidation. At the molecular level, more oxidized, aromatic DOM formulas are associated with oxygen consumption and DIC production. Bulk level measurements indicate that DOM becomes less aromatic and lower in apparent molecular weight following partial photooxidation, and there is molecular level evidence of oxygen addition and loss of CO2 in all samples. However, formulas most susceptible to photooxidation vary depending on the initial DOM composition. Collectively, this work provides insights into the relationship between DOM composition and photooxidation, which has important implications for carbon cycling in diverse surface waters.