Argon Power Cycle (APC) combustion engine has a high efficiency, zero carbon emissions, and zero pollutant emissions, rendering it a promising way for achieving zero or carbon neutrality within the realm of internal combustion engine (ICE) technology. Previous studies have shown that while APCs significantly improve the thermal efficiency of ICEs, they also face serious knock problems due to their high temperatures and pressures, especially when hydrogen is used as a fuel. In this study, the anti-knocking characteristics of hydrogen, methane, carbon monoxide, and ammonia were first investigated in APC through thermodynamic calculations by Ignition Delay Time. Then, based on testbench experiments, hydrogen and methane fuels were selected to further investigate the effect of different fuel anti-knocking characteristics on the indicated thermal efficiency and power of APC combustion engine. Test results showed that when using hydrogen, the APC ICE exhibited a pronounced knock tendency, and the test engine could not operate stably when the excess oxygen ratio <2.1 at compression ratio = 9.6. The CA50 of the maximum efficiency point was delayed in APC than in air for both hydrogen and methane, specially H2 has an obvious lag at about 5–15 ° CA. In comparison, when using methane, the combustion control of engine is easier, and the peak indicated thermal efficiency 59% and the peak indicated mean effective pressure 0.92 MPa are higher than 54.3% and 0.60 MPa of using hydrogen. The use of hydrogen still needs an anti-knocking strategy while an extra carbon capture device is necessary to ensure a closed argon cycle if methane is employed.