The accumulation of bilirubin in the body could cause nervous system diseases and even endanger life in severe cases for people with liver damage or metabolic obstruction. Hemoperfusion has been considered as one of the most efficient treatments to remove extra bilirubin. Although, the current bilirubin adsorbents could adsorb the free bilirubin effectively, the albumin-bound bilirubin in plasma is hard to remove. Here, we develop a 3D nanofiber sponge fabricated by combination of electrospinning and improved gas-foaming techniques. The amino groups and BSA molecules were immobilized on the fiber surface as the affinity groups to adsorb bilirubin. The 3D nanofiber sponges have layered structure and significantly higher porosity than two-dimensional nanofiber membranes. The special 3D structure renders the sponge fully contact with the adsorbed liquid and reduces the diffusion distance of the adsorbate, thus increases the sponge's adsorption rate. The BSA immobilized nanofiber sponge showed large adsorption capacity in both aqueous solution (maximum adsorption capacity was 36.8237 mg/g) and plasma (maximum adsorption capacity was 25.2908 mg/g), rapid adsorption rate (achieved adsorption equilibrium in 60 min) and well blood compatibility.