AbstractIn this work, the hydrophobically modified alginate derivative (HMAD) was synthesized by using sodium alginate, cyclohexyl isocyanide, octylamine and propionaldehyde instead of formaldehyde, based on previous explorations of the Ugi reaction for the modification of alginate. Experimental results revealed that the successful grafting of the hydrophobic chains onto the alginate molecular backbone via the Ugi reaction had weakened and destroyed the intramolecular hydrogen bonds, thus enhancing the molecular flexibility of alginate, which endowed the HMAD with good amphiphilic property with the critical aggregation concentration (CAC) of 0.44 g/L. Moreover, the resultant HMAD could form the stable self‐aggregated micelles with the spherical shape due to the intra or intermolecular hydrophobic associations. Its average hydrodynamic diameter and zeta potential were 458 nm (PDI=0.26) and −61.4 mV, respectively, which was able to achieve the loading and sustained‐release of hydrophobic ibuprofen. Meanwhile, HMAD had no significant cytotoxicity to the murine macrophage RAW264.7 cells. Based on the above merits, the synthesized HMAD could exhibit great potential for the development of hydrophobic pharmaceutical formulations.