An efficient domino annulation strategy for the synthesis of 3-acylated 1-aminoisoquinolin-4-ols has been developed from readily available 2-formylbenzonitriles and α-azidoketones under mild basic conditions. The reaction proceeds through a cascade sequence of aldol condensation, imine formation, tautomerization, and cycloisomerization to afford highly functionalized aminopyridinol-containing heterocycles.