Peptides and peptidomimetics are emerging as an important class of clinic therapeutics. Here we report a peptide-guided method for the functionalization and macrocyclization of bioactive peptidosulfonamides by Pd(II)-catalyzed late-stage C-H activation. In this protocol, peptides act as internal directing groups and enable site-selective olefination of benzylsulfonamides and cyclization of benzosulfonamides to yield benzosultam-peptidomimetics. Our results provide an unusual example of benzosulfonamide cyclization with olefins through a sequential C-H activation, which involves the generation of a reactive palladium-peptide complex. Furthermore, this protocol allows facile self-guided macrocyclization of sulfonamide-containing peptides by intramolecular olefination with acrylates and unactivated alkenes, affording bioactive peptidosulfonamide macrocycles of various sizes. Together, our results highlight the utility of peptides as internal directing groups in facilitating transition metal-catalyzed functionalization of peptidomimetics.