A novel approach has been established for synthesizing novel structurally diverse azo disperse dyes with good fastness properties by employing Ugi four-component reaction as the key step. 15 new disperse azo dyes were synthesized efficiently from readily available starting materials with simple operations through a sequence of generation of 4-(2-(ethyl (phenyl)amino)ethoxy)-4-oxobutanoic acid, the Ugi four-component reactions of the acid with anilines, benzaldehydes and cyclohexyl isocyanide, and the coupling of the Ugi adducts with aryl diazonium salts. The structures of Ugi adducts and the new dyes were fully characterized with ¹H NMR, ¹³C NMR, IR, MS, and HRMS. Visible absorption measurements and molar extinction coefficients were also carried out. It was found that the obtained dyes exhibited improved fastness properties on both polyamide (PA) and poly(ethylene terephthalate) (PET) fabrics as compared with C. I. Disperse Red 1 and C. I. Disperse Red 13. The improvement of fastness properties should be attributed to the introduced two amides and one ester functionalities, and the appropriately increased molecular weight/size. It is an attractive approach for accessing a library of novel azo disperse dyes with good fastness properties.