Photodegradation greatly affects everyday life. It poses challenges when food deteriorates or when objects of cultural heritage fade, but it can also create opportunities applied in advanced oxidation processes in water purification. Studying photodegradation, however, can be difficult because of the time needed for degradation, the inaccessibility of pure compounds, and the need to handle samples manually. A novel light-exposure cell, based on liquid-core-waveguide (LCW) technology, was embedded in a multiple-heart-cut two-dimensional liquid chromatography system by coupling the LCW cell to the multiple-heart-cut valve. The sample was flushed from the heart-cut loops into the cell by an isocratic pump. Samples were then irradiated using different time intervals and subsequently transferred by the same isocratic pump to a second-dimension sample loop. The mixture containing the transformation products was then subjected to the second-dimension separation. In the current setup, about 30–40% of the selected fraction was transferred. Multiple degradation products could be monitored. Degradation was found to be faster when a smaller sample amount was introduced (0.3 μg as compared to 1.5 μg). The system was tested with three applications, that is, fuchsin, a 19th-century synthetic organic colorant, annatto, a lipophilic food dye, and vitamin B complex.