This paper presents a facile and low-cost strategy for fabrication lysozyme-loaded mesoporous silica nanotubes (MSNTs) by using silk fibroin (SF) nanofiber templates. The “top-down method” was adopted to dissolve degummed silk in CaCl₂/ formic acid (FA) solvent, and the solution containing SF nanofibrils was used for electrospinning to prepare SF nanofiber templates. As SF contains a large number of -OH, -NH₂ and -COOH groups, the silica layer could be easily formed on its surface by the Söber sol-gel method without adding any surfactant or coupling agent. After calcination, the MSNTs were obtained with inner diameters about 200 nm, the wall thickness ranges from 37 ± 2 nm to 66 ± 3 nm and the Brunauer–Emmett–Teller (BET) specific surface area was up to 200.48 m²/g, the pore volume was 1.109 cm³/g. By loading lysozyme, the MSNTs exhibited relatively high drug encapsulation efficiency up to 31.82% and an excellent long-term sustained release in 360 h (15 days). These results suggest that the MSNTs with the hierarchical structure of mesoporous and macroporous will be a promising carrier for applications in biomacromolecular drug delivery systems.