The Cabibbo-suppressed decay Λb 0 → ψ(2S)pπ− is observed for the first time using a data sample collected by the LHCb experiment in proton-proton collisions corresponding to 1.0, 2.0 and 1.9 fb−1 of integrated luminosity at centre-of-mass energies of 7, 8 and 13 TeV, respectively. The ψ(2S) mesons are reconstructed in the μ+μ− final state. The branching fraction with respect to that of the Λb 0 → ψ(2S)pK− decay mode is measured to be ℬ(Λb0→ψ(2S)pπ−)ℬ(Λb0→ψ(2S)pK−)=(11.4±1.3±0.2)%, where the first uncertainty is statistical and the second is systematic. The ψ(2S)p and ψ(2S)π− mass spectra are investigated and no evidence for exotic resonances is found.[Figure not available: see fulltext.].