The rational design of efficient electrode materials for fuel cells, water oxidation, and metal-air batteries is now cutting-edge activity in renewable energy research. In this regard, tuning activity at the molecular level is one of the most challenging problems. Here, we have strategically employed two isophthalate-based ligands to tune the molecular structure and chemical bonding of three Co-based MOFs at the atomic level. MOFs were well characterized by single-crystal X-ray diffraction, IR spectroscopy, and X-ray absorption spectroscopy. The assembly of Co in these three novel MOFs at the atomic level dictates the catalytic activity towards the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). The catalytic activity of these MOFs has been boosted further upon annealing thereby forming highly efficient noble-metal-free Co-single atom catalysts where the amount of cobalt is extremely low.