Co−Mn catalysts have long been considered as a promising catalyst for Fischer‐Tropsch synthesis (FTS). However, the promotional role of Mn and its interaction with Co remain unclear and controversial. In situ characterization of the structural change of FTS catalysts is a powerful way to reveal the reaction mechanisms. Nevertheless, there are significant difficulties because of the harsh reaction conditions. Here, the microstructure evolution of Co/MnO catalysts during FTS is monitored by in situ X‐ray absorption fine structure (XAFS) spectroscopy under real FTS atmosphere up to 6 bar for the first time. Combined with in situ X‐ray diffraction (XRD), ex situ high‐angle annular dark‐field scanning transmission electron microscopy (HAADF‐STEM) and H2 chemisorption characterizations, we reveal that the metallic Co liberated from Mn1−xCoxO during FTS leads to activity enhancement. The presence of Mn improves the Co dispersion. However, an initial association of Mn with the Co phase hampers the cobalt reducibility. We also find that increasing the reaction pressure enhances the oxygen dissociation on the Mn surface, which leads to an increased number of exposed Co sites and consequent FTS activity improvement.