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COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1β in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.