Marine oil spills have devastating consequences for marine and coastal ecosystems. When a spill happens in the vicinity of natural oil seeps, assessment and remediation are especially difficult. Extensive research on the rates of crude oil degradation in different environments has been conducted, primarily on the effects of microbial degradation, but less is understood regarding the photo-oxidation processes that also occur. In May 2015 a rupture of a pipeline at Refugio State Beach, CA, resulted in the release of crude oil into the ocean in the vicinity of naturally occurring oil seeps. In this study, long-term experiments were conducted in filter-sterilized seawater to better understand the effects of photochemical processes on the dissolution and chemical persistence of oil-derived compounds in the water column, from both industrial crude and natural seep oil. Due to the known chemical composition and properties of oil, fluorescence properties and dissolved organic carbon (DOC) concentrations were measured to evaluate slick dissolution and abiotic photochemical degradation. When the oil slick was present throughout the experiment, fluorescent peak intensities of irradiated spill oil samples increased to values three times higher than their dark counterparts and the irradiated seep oil samples. Similarly, DOC concentrations measured in the first 20 days of irradiation were significantly higher in irradiated spill oil samples (125 ± 9.1 mg/L) than in irradiated seep oil samples (87 ± 13 mg/L; p = 0.025), reflecting the higher dissolution rates of spill oil compared to seep oil. Under dark conditions, DOC concentrations increased slightly throughout the experiment for both oil types. Nontargeted analysis based on comprehensive two-dimensional gas chromatography coupled with time of flight mass spectroscopy (GC×GC/TOF-MS) identified 488 and 150 statistically significant compounds that were persistent through the 67-day experiment in the spill and seep oil samples, respectively. Photosensitivity was higher in the seep samples, but ultimately all analyses showed photochemical processes aided in the dissolution of oil-derived constituents and had little influence on the transformation or degradation of compounds that entered the water column. These findings have important implications for the modeling of persistence and degradation of dissolved constituents from oil spills and seeps.