Iron is an essential element in nonheme enzymes that plays a crucial role in many vital oxidative transformations and metabolic reactions in the human body. Many of those reactions are regio‐ and stereospecific and it is believed that the selectivity is guided by second‐coordination sphere effects in the protein. Here, we show results on a few engineered biomimetic ligand frameworks based on the N4Py scaffold (N,N‐bis(2‐pyridylmethyl)‐N‐bis(2‐pyridyl)methylamine) and study the second‐coordination sphere effects. We show here, for the first time, that selective substitutions in the ligand framework can tune the catalytic properties of the iron(IV)‐oxo complexes by regulating the steric and electronic factors. In particular, a better positioning of the oxidant and substrate in the rate‐determining transition state lowers the reaction barriers. Therefore, an optimum balance between steric and electronic factors mediates the ideal positioning of oxidant and substrate in the rate‐determining transition state that affects the reactivity of high‐valent reaction intermediates.