Daphnetin (7,8-dihydroxy-coumarin, DAPH) is a naturally occurring coumarin presenting a wide array of biological activities. In the present study, daphnetin and its novel synthetic analogue 7,8-dihydroxy-4-methyl-3-(4-hydroxyphenyl)-coumarin (DHC) were encapsulated in solid lipid nanoparticles (SLNs) with Encapsulation Efficiency values of 80% and 40%, respectively. Nanoparticles of an average hydrodynamic diameter of approximately 250 nm were formed, showing a good stability in aqueous dispersion (polydispersity index 0.3–0.4), as determined by Dynamic Light Scattering (DLS). The SLNs were also characterized using Fourier Transform-Infrared (FT-IR) spectroscopy and Thermogravimetric Analysis (TGA). TEM images of the blank-SLNs indicated a spherical morphology and a size of 20–50 nm. The release studies of the coumarin analogues indicated a non-Fickian diffusion mechanism, while the release profiles better fitted on the Higuchi kinetic model. Moreover, the coumarin analogues and their SLNs were examined for their antioxidant activity using DPPH and anti-lipid peroxidation assays, exhibiting stronger antioxidant activity when encapsulated than in their free form. The coumarin derivatives and their SLNs were examined for their photodynamic therapy (PDT) efficacy against the human squamous carcinoma A431 cell line, with DHC coumarin both in its free and encapsulated form exhibiting significant PDT activity, reducing the cell viability to 11% after irradiation with a fluence rate of 2.16 J/cm2. Finally, the intracellular localization studies indicated the enhanced cellular uptake of the coumarin analogues when loaded in the SLNs.