Solid lipid nanoparticles (SLNs) are essentially composed of triglyceride(s) that orient to form a polar core with polar heads oriented toward the aqueous phase, resembling chylomicrons. The composition of such SLNs may alter the course of drug absorption predominantly to and through lymphatic route and regions, presumably following a transcellular path of lipid absorption, especially by enterocytes and polar epithelial cells of the intestine. SLNs were prepared using stearic acid, glycerol monostearate, tristearin, and Compritol 888 ATO by solvent diffusion method using demineralized double-distilled water as the dispersion medium. The SLNs were characterized for shape, size, zeta potential, and percentage drug content and its release. The characterization of SLNs suggests that Compritol 888 ATO-based nanoparticles were heterogeneous with better drug-loading and release characteristics as compared with the other formulations. The selected products were studied for in vivo absorption and hence bioavailability by measure of area under the blood plasma curve plotted as a function of time. Periodic lymphatic concentration of drug following oral administration of respective formulations was also determined by mesenteric duct cannulation and collection of samples. The comparative study conducted on methotrexate (MTX)-bearing SLNs revealed that the formulation based on Compritol 888 ATO could noticeably improve the oral bioavailability of MTX, presumably following SLNs constituting lipid digestion and co-absorption through lymphatic transport and route.