Separators have an important influence on the safety and performance of lithium-ion batteries (LIBs). However, traditional polyolefin-based separators suffer from poor thermal stability and weak electrolyte wettability. Here, by using hydroxyapatite (HAP) and cellulose nanofibers (CNFs) as raw materials, we fabricated a unique HAP/CNF hybrid separator. The separators exhibit excellent thermal properties, with high thermal stability (up to 250 °C) and outstanding flame retardancy. The separators also demonstrate excellent electrolyte wettability. Compared to polypropylene (PP) separators, the HAP/CNF separators show a smaller contact angle with electrolytes, 17.2° for HAP/CNF and 45.5° for PP. Meanwhile, the HAP/CNF separators illustrate an excellent smoothness of 68.0 nm. In addition, the batteries assembled with the hybrid separators display a better performance compared with the batteries assembled with commercial PP separators. The raw materials are green, and the fabrication processes are free of organic solvents. We envision that the HAP/CNF hybrid separator could be a promising separator candidate for next-generation high-safety and high-performance LIBs.