Although the negative impact of long‐duration spaceflight on spine BMD has been reported, its impact on vertebral strength and risk of vertebral fracture remains unknown. This study examined 17 crewmembers with long‐duration service on the International Space Station in whom computed tomography (CT) scans of the lumbar spine (L1 and L2) were collected preflight, immediately postflight and 1 to 4 years after return to Earth. We assessed vertebral strength via CT‐based finite element analysis (CT‐FEA) and spinal loading during different activities via subject‐specific musculoskeletal models. Six months of spaceflight reduced vertebral strength by 6.1% (−2.3%, −8.7%) (median [interquartile range]) compared to preflight (p  < 0.05), with 65% of subjects experiencing deficits of greater than 5%, and strengths were not recovered up to 4 years after the mission. This decline in vertebral strength exceeded (p  < 0.05) the 2.2% (−1.3%, −6.0%) decline in lumbar spine DXA‐BMD. Further, the subject‐specific changes in vertebral strength were not correlated with the changes in DXA‐BMD. Although spinal loading increased slightly postflight, the ratio of vertebral compressive load to vertebral strength for typical daily activities remained well below a value of 1.0, indicating a low risk of vertebral fracture despite the loss in vertebral strength. However, for more strenuous activity, the postflight load‐to‐strength ratios ranged from 0.3 to 0.7, indicating a moderate risk of vertebral fracture in some individuals. Our findings suggest persistent deficits in vertebral strength following long‐duration spaceflight, and although risk of vertebral fracture remains low for typical activities, the risk of vertebral fracture is notable in some crewmembers for strenuous exercise requiring maximal effort.