Oxygen electrocatalysis plays a critical role in the efficiency of important energy conversion and storage systems. While many efforts have focused on designing efficient electrocatalysts for these processes, optimal catalysts that are inexpensive, active, selective, and stable are still being searched. Nonstoichiometric, mixed-metal oxides present a promising group of electrocatalysts for these processes due to the versatility of the surface composition and fast oxygen conducting properties. Herein, we demonstrate, using a combination of theoretical and experimental studies, the ability to develop design principles that can be used to engineer oxygen electrocatalysis activity of layered, mixed ionic-electronic conducting Ruddlesden-Popper (R-P) oxides. We show that a density function theory (DFT) derived descriptor, O-2 binding energy on a surface oxygen vacancy, can be effective in identifying efficient R-P oxide structures for oxygen reduction reaction (ORR). Using a controlled synthesis method, well-defined nanostructures of R-P oxides are obtained, which along with thermochemical and electrochemical activity studies are used to validate the design principles. This has led to the identification of a highly active ORR electrocatalyst, nanostructured Co-doped lanthanum nickelate oxide, which when incorporated in solid oxide fuel cell cathodes significantly enhances the performance at intermediate temperatures (similar to 550 degrees C), while maintaining long-term stability. The reported findings demonstrate the effectiveness of the developed design principles to engineer mixed ionic-electronic conducting oxides for efficient oxygen electrocatalysis, and the potential of nanostructured Co-doped lanthanum nickelate oxides as promising catalysts for oxygen electrocatalysis.