<p>Disrupting the symmetric electron distribution of porphyrin-like Fe single-atom catalysts has been considered as an effective way to harvest high intrinsic activity. Understanding the catalytic performance governed by geometric microstrains is highly desirable for further optimization of such efficient sites. Here, we decipher the crucial role of local microstrain in boosting intrinsic activity and durability of asymmetric Fe single-atom catalysts (Fe–N₃S₁) by replacing one N atom with S atom. The high-curvature hollow carbon nanosphere substrate introduces 1.3% local compressive strain to Fe–N bonds and 1.5% tensile strain to Fe–S bonds, downshifting the <i>d</i>-band center and accelerating the kinetics of *OH reduction. Consequently, highly curved Fe–N₃S₁ sites anchored on hollow carbon nanosphere (FeNS-HNS-20) exhibit negligible current loss, a high half-wave potential of 0.922&#xa0;V vs. RHE and turnover frequency of 6.2 e⁻¹&#xa0;s⁻¹ site⁻¹, which are 53&#xa0;mV more positive and 1.7 times that of flat Fe–N–S counterpart, respectively. More importantly, multiple operando spectroscopies monitored the dynamic optimization of strained Fe–N₃S₁ sites into Fe–N₃ sites, further mitigating the overadsorption of *OH intermediates. This work not only sheds new light on local microstrain-induced catalytic enhancement, but also provides a plausible direction for optimizing efficient asymmetric sites via geometric configurations.</p><p></p>