The increased expression of heat shock protein (Hsp)60 in different kinds of graft tissues has been associated with a proinflammatory role and rejection. However, there are very few reports in which treatment with Hsp60 delays skin allograft rejection. The aim of this work was to evaluate the capacity of encapsulated human Hsp60‐derived peptide p277 to delay graft rejection in two murine models of skin transplantation with minor antigen disparities. Briefly, BALB/c mice and C57BL/6 were intranasally pre‐treated with five doses of Hsp60 p277 peptide encapsulated in polylactide‐co‐glycolide acid microspheres (PLGM), and received skin grafts from DBA2 mice and 129/B6 (F1) mice respectively. The treatment with the peptide increased skin graft survival more than 20 days in both the mouse strains, mainly in C57BL/6 recipients (P < 0.05). Also, p277‐treated BALB/c and C57BL/6 mice showed IL‐10 and IFN‐γ production, induced by p277 peptide. For the first time, a mucosal schedule using the Hsp60 C‐terminal peptide p277 encapsulated in PLGM showed some survival prolongation of skin grafts bearing minor antigen disparities. Our results suggest a potential role for Hsp60‐based therapy and the mucosal route as a useful tool to control the inflammatory response to allografts.