Space fission reactors can provide reliable, high power levels for periods of more than 10 years to support human outposts and for space travel to the farthest planets in the solar system. The operation lifetimes of these reactors depend on many factors chief among which are the hot‐clean excess reactivity and the fuel burnup rate (or operation power) and the accumulation and decay of fission products. Other important parameters are the fuel average temperature and fissile inventory and the Doppler reactivity effect. Determining the operation lifetime for space reactors is a critical input to mission planning, requiring the use of sophisticated fuel burnup and criticality computational tools and benchmarking the results against actual data, if readily available. This paper performs parametric and comparative studies using widely used codes and a simplified approach for determining the operation lifetimes of two space reactors: the Sectored, Compact Reactor (SCoRe) that is liquid metal cooled, and the Submersion‐Subcritical, Safe Space (S∧4) reactor that is cooled by a He‐Xe binary gas mixture. The codes investigated against experimental data from a LWR are: (a) Monteburns 2.0, coupling MCNP5 1.30 to Origen2.2, (b) MCNPX 2.6b’s internal burn package incorporating CINDER90, and (c) TRITON a code in the SCALE5 package using NEWT and Origen‐S. From the results Monteburns and MCNPX performed the best, and are selected to compare their predictions of the lifetimes of the two space reactors with those of a simplified method. This method couples MCNP5 to a burnup analysis model in Simulink® considering only the 10 most probable low Z and 10 most probable high Z elements of the fission yield peaks plus 149Sm. Results show that the predicted operational lifetimes using the simplified method are within −6.6 to 12.8% of those calculated using the widely used Monteburns 2.0 and MCNPX 2.6bc1 codes.