Actinomycetes of the genus Rhodococcus (class Actinomycetia) are dominant dwellers of biotopes with anthropogenic load. They serve as a natural system of primary response to xenobiotics in open ecosystems, initiate defensive responses in the presence of pollutants, and are regarded as ideal agents capable of transforming and degrading pharmaceuticals. Here, the ability of selected Rhodococcus strains to co-metabolize nonsteroidal anti-inflammatory drugs (ibuprofen, meloxicam, and naproxen) and information on the protective mechanisms of rhodococci against toxic effects of pharmaceuticals, individually or in a mixture, have been demonstrated. For the first time, R. ruber IEGM 439 provided complete decomposition of 100 mg/L meloxicam after seven days. It was shown that versatile cellular modifications occurring at the early development stages of nonspecific reactions of Rhodococcus spp. in response to separate and combined effects of the tested pharmaceuticals included changes in electrokinetic characteristics and catalase activity; transition from unicellular to multicellular life forms accompanied by pronounced morphological abnormalities; changes in the average size of vegetative cells and surface area-to-volume ratio; and the formation of linked cell assemblages. The obtained data are considered as adaptation mechanisms in rhodococci, and consequently their increased resistance to separate and combined effects of ibuprofen, meloxicam, and naproxen.