In this work, the influence of imidazolium ionic liquids (ILs) on bio-chemical parameters that influence the in vivo behavior of nimesulide was evaluated. In this context, the binding of nimesulide to human serum albumin (HSA), in IL media, was studied. In parallel, the evaluation of the interaction of drug–IL systems, with micelles of hexadecylphosphocholine (HDPC), enabled the calculation of partition coefficients (Kp). Both assays were performed in buffered media in the absence and in the presence of emim BF4, emim Ms and emim TfMs 1%. Even though there was an increase of the dissociation constant (Kd) in IL media, nimesulide still binds to HSA by means of strong interactions. The thermodynamic analysis indicates that the interaction is spontaneous for all the tested systems. Moreover, the studied systems exhibited properties that are favorable to the interaction of the drug with biological membranes, with Kp values 2.5–3.5 higher than in aqueous environment. The studied nimesulide–IL systems presented promising characteristics regarding the absorption and distribution of the drug in vivo, so that the studied solvents seem to be good options for drug delivery.