Paracetamol is considered a priority pharmaceutical because its presence in the environment may have an impact on human health and in food chains. To remediate this problem, the use of Solanum nigrum L. plants for the clean-up of paracetamol-contaminated sites was investigated. The study revealed that this plant species can be used as a remarkable paracetamol phytoremediation instrument, thus delivering a cost-effective and eco-friendly cleanup technology for its environmental removal. Paracetamol was not toxic to plants, exerting a growth-promoting effect up to 0.5 mg L−1. Plant tolerance mechanisms resided essentially on root GST-mediated conjugation of paracetamol to GSH, powered by the γ-ECS increased activity that locally provided the GSH needed. Increased activities for GST and γ–ECS were detected in roots and shoots of treated plants and these enzymes were regulated in an organ- and gene-specific manner: at the transcription level in roots and post-transcriptionally in shoots, with GSTs of the classes Theta and Phi playing the most relevant role in the plant detoxification process.