Niosomes have been reported to deliver the drug at a lower concentration over prolonged period of time to the target site and so reducing the potential dose related side effects. The purpose of the present study was to prepare, characterize and optimize Ketorolac Tromethamine (KT) niosomes for topical applications. This could be achieved by using ether injection method for preparing niosomes applying Box-Behnken design to choose these formulae. Box-Behnken design determined fifteen formulae containing specified amounts of independent variables, which included hydrophilic lipophilic balance (HLB) (X1), percent of cholesterol-surfactant concentration in total lipid (X2) and Lipid drug concentration (X3). The dependent variables studied were entrapment efficiency of KT niosomes (Y1), cumulative percent releases after one hour (Y2), six hours (Y3) and twelve hours (Y4). The prepared niosomes were characterized for their entrapment efficiency, shape and morphology by using scanning electron microscope (SEM) and in vitro release studies of Ketorolac Tromethamine. The data obtained showed that increasing HLB (X1) values resulted in decrease entrapment efficiency (Y1) and increase cumulative percent releases after one hours (Y2), six hours (Y3) and twelve hours (Y4). In contrast the results indicated that increasing both percent of cholesterol-surfactant concentration in total lipid (X2) and Lipid drug concentration (X3) from lower to higher levels resulted in increase entrapment efficiency (Y1) and decrease cumulative percent releases after one hours (Y2), six hours (Y3) and twelve hours (Y4). Kinetic treatment of the in vitro release from drug loaded niosomes indicated that the higuchi diffusion is the drug release mechanism for the most formulae.