SOFC/SOEC) functioning at elevated temperature, [1][2][3][4] electrochemical water splitting in aqueous solution, [5][6][7] and advanced oxidation processes for water treatment. [8] However, perovskite-based materials synthesized via the conventional solid-state reaction methods typically show large particle size due to high sintering temperature, thus resulting in poor catalytic performance.To enhance the device performance, various techniques have been developed to synthesize perovskite-based oxide catalysts with nanostructure. [9][10][11][12][13][14][15][16] For instance, Chen et al. [17] synthesized a hierarchically porous nano network (Sm 0.5 Sr 0.5 CoO 3 -Gd 0.1 Ce 0.9 O 2-δ ) as a cathode of SOFC, which strongly enhanced the power density and stability of the devices. Similarly, Ahn et al. [13] reported that SOFC with Sm 0.5 Sr 0.5 CoO 3-δ nanofiber-based composite cathode showed a significantly lower area specific resistance compared to one with SSC powder cathode. Zhao et al. observed strongly boosted oxygen evolution reaction (OER) activity of PrBa 0.5 Sr 0.5 Co 1.5 Fe 0.5 O 5+δ (PBSCF) nanotube in alkaline solution as they shrank the material size to tens of nanometers. [14] Although all these works demonstrate that nanostructure engineering can be an effective approach for improving the catalytic activity of perovskite-based oxide, the mechanism for the enhancement is still not fully understood. In most cases, the improved performance was attributed to Perovskite-based oxides attract great attention as catalysts for energy and environmental devices. Nanostructure engineering is demonstrated as an effective approach for improving the catalytic activity of the materials. The mechanism for the enhancement, nevertheless, is still not fully understood. In this study, it is demonstrated that compressive strain can be introduced into freestanding perovskite cobaltite La 0.8 Sr 0.2 CoO 3−δ (LSC) nanofibers with sufficient small size. Crystal structure analysis suggests that the LSC fiber is characterized by compressive strain along the ab plane and less distorted CoO 6 octahedron compared to the bulk powder sample. Accompanied by such structural changes, the nanofiber shows significantly higher oxygen reduction reaction (ORR) activity and better stability at elevated temperature, which is attributed to the higher oxygen vacancy concentration and suppressed Sr segregation in the LSC nanofibers. First-principle calculations further suggest that the compressive strain in LSC nanofibers effectively shortens the distance between the Co 3d and O 2p band center and lowers the oxygen vacancy formation energy. The results clarify the critical role of surface stress in determining the intrinsic activity of perovskite oxide nanomaterials. The results of this work can help guide the design of highly active and durable perovskite catalysts via nanostructure engineering.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smll.202104144.