Austenitic stainless steel 316H is considered a promising structural material for lead-bismuth-cooled fast reactors (LFRs), owing to its superior high-temperature mechanical properties, creep resistance, and radiation tolerance. This study systematically investigates the creep-fatigue-oxidation (CFO) behavior of 316H stainless steel in oxygen-saturated lead-bismuth eutectic (LBE) at 550–600 °C, with an emphasis on the coupled influence of environmental exposure and holding time during cyclic loading. Results reveal that under short holding times (<300 s), the fatigue life in LBE is significantly degraded, with a reduction by a factor of 5 to 10 compared to that in air. This degradation is primarily attributed to premature crack initiation and accelerated propagation caused by unstable oxide films and the ingress of LBE. As the holding time increases (>300 s), the damage evolution transitions from transgranular to intergranular, accompanied by the formation of a dense and protective duplex oxide layer that effectively mitigates further degradation. Microstructural and compositional analyses confirm that the oxide layer acts as a diffusion barrier, retarding LBE penetration and contributing to fatigue life recovery. The results highlight the complex interactions between creep, fatigue, and oxidation, and offer insight into CFO mechanisms under realistic service conditions, thereby providing a basis for life assessment and material selection in LFRs systems.