Cellulose nanofibers (CNFs) are highly promising nanocarrier materials, boasting excellent drug adsorption and loading potential due to their tunable hydrophilic/lipophilic interfaces. This study is the first to report the successful synthesis of maleic anhydride-modified CNFs (MA-CNFs) via the esterification of CNFs using a solvent-free molten maleic anhydride (MA) system, and it systematically evaluates MACNFs’ dual adsorption performance for water-soluble and lipophilic drugs. A new characteristic peak at 1723 cm⁻¹ in FT-IR confirms the formation of ester bonds, proving the successful grafting of MA onto CNFs. XRD analysis shows that the crystallinity slightly increases from 72.56% to 74.06%, indicating the reaction mainly occurs in the amorphous region. After modification, the material’s hydrophobicity is significantly enhanced (water contact angle: ~63.3° for CNFs vs. ~74.9° for MA-CNFs), and its BET specific surface area rises sharply from 5.03 to 26.29 m²/g. These structural advantages collectively enable MA-CNFs to have adsorption capacities for folic acid (FA, water-soluble) and vitamin E acetate (VEA, lipophilic) that are 1.15 and 2.04 times those of CNFs, respectively. The results demonstrate MA-CNFs are high-performance functional materials fabricated via a green method, with good biocompatibility.