Exploited in radiation environments, including space, nuclear reactors and large accelerators, fibers would experience significant parameter change induced by the interaction with radiation, including radiation induced attenuation, radiation induced refractive index change, radiation induced lifetime change and radiation induced luminescence, which would then result in severe performance degradation of the fiber laser system. Here, the response characteristics of Yb-doped fiber lasers to gamma-ray radiation are investigated through both experiments and simulations. The performance variation of various fiber components after gamma radiation, including passive fiber, pump combiner, fiber Bragg grating and active fiber, is studied and compared with an accumulated total dose up to 1000 Gy. And, experiments show that, in a fiber laser system, the active fiber is the most sensitive part to gamma radiation, while various passive fiber components show negligible response. Then, impacts of cavity configuration parameters, such as pump scheme and active fiber length, on the response of fiber lasers are explored through series of radiation experiments. It’s shown that, compared to forward pump, backward pump scheme helpful to improve the radiation-resistant capability of fiber lasers. And, lasers with relatively shorter active fiber show smaller power drop when operated in radiation situations. Besides, corresponding simulations are carried out with the previously developed multi-physics thermal model considering hundred-watt level Yb-doped fiber lasers, demonstrating consistent results with the experiments. This research should be instructive for the design optimization of fiber laser systems operated in radiation environments.