K-ion batteries (KIBs) hold great promise for large-scale energy storage. However, the absence of suitable cathode materials limits their practical application. Meanwhile, rationally designing advanced cathode materials for KIBs remains an open question. In this work, based on density functional theory calculations, we find that the bond stability of Fe−O is higher than that of Co−O in layered transitional metal (TM) oxides. Additionally, the K-ion migration in the Fe-based layered TM oxide has a significantly lower activation energy barrier than that in the Co-based one. Based on this theoretical prediction, we successfully synthesized a low-cost K0.45Ni0.1Fe0.1Mn0.8O2 cathode, which shows excellent structural stability and superior K-storage properties, including durable cycle life and high-rate capability. Moreover, the designed K0.45Ni0.1Fe0.1Mn0.8O2 cathode possesses a great full-cell performance with a discharge capacity of ∼75 mA h g−1 and capacity retention of ∼80% after 100 cycles. The results show that Fe has better structural stability and K-ion diffusion than high-cost Co in layered oxide cathodes, and this finding provides new insights into the design of low-cost and high-performance KIB layered cathodes. This work highlights the feasibility of a theory-guided experiment in screening promising battery materials.