Musculoskeletal loss in actual or simulated microgravity occurs at a high rate. Bed rest studies are a reliable ground based spaceflight analogue that allow for direct comparison of intervention and control participants. The aim of this review was to investigate the impact of exercise compared to no intervention on bone mineral density (BMD) and muscle cross-sectional area (muscle CSA) in bed rest studies relative to other terrestrial models. Eligible bed rest studies with healthy participants had an intervention arm with an exercise countermeasure and a control arm. A search strategy was implemented for MEDLINE. After screening, eight studies were identified for inclusion. Interventions included resistive exercise (RE), resistive vibration exercise (RVE), flywheel resistive exercise, treadmill exercise with lower body negative pressure (LBNP) and a zero-gravity locomotion simulator (ZLS). Lower limb skeletal sites had the most significant BMD losses, particularly at the hip which reduced in density by 4.59% (p<0.05) and the tibial epiphysis by 6% (p<0.05). Exercise attenuated bone loss at the hip and distal tibia compared to controls (p<0.05). Muscle CSA changes indicated that the calf and quadriceps were most affected by bed rest. Exercise interventions significantly attenuated loss of muscle mass. ZLS, LBNP treadmill and RE significantly attenuated bone and muscle loss at the hip compared to baseline and controls. Despite exercise intervention, high rates of bone loss were still observed. Future studies should consider adding bisphosphonates and pharmacological/nutrition-based interventions for consideration of longer-duration missions. These findings correlate to terrestrial bed rest settings, for example, stroke or spinal-injury patients.