Purpose Niosomes as vesicular frameworks are novel methods of delivering a drug in a sustained manner to enhance its bioavailability and get therapeutic effect over a longer period time. This study conclusively demonstrates the preparation, characterization, and optimization of sustained release ketorolac tromethamine (KT) niosomal organogels to enhance skin permeation and increase drug efficacy. Methods The ether injection method was used to compose 15 formulae of KT niosomes containing adequate concentrations of unbiased variables. Those variables included hydrophilic-lipophilic balance value (HLB), cholesterol ratio in total lipid (Chol. Ratio), and the ratio of total lipid to the drug (L:D Ratio). The response surface technique was used to investigate the impact of those variables on entrapment efficiency percentage (EE %) of KT niosomes (Y1) and cumulative percentage releases after 6 h (% Rel6) (Y2) and 12 h (% Rel12) (Y3), which are selected as dependent variables. Results The prepared KT niosomes were round in shape and have a diameter of 100–500 nm. No drug/excipient interaction has occurred either in the physical mixture or KT-loaded niosomes. Optimum drug release pattern was obtained at low HLB level, while Chol. Ratio and L: D Ratio should be at high levels. The entrapment efficiency of the optimized formula of KT niosomes was found to be equal to 40.13%, while the cumulative percent release of KT after 6 and 12 h reached 52.3% and 74.5%, respectively. Significant anti-inflammatory effect is shown with niosomal organogel (85% pow edema inhibition) which is in positive correlation with in vitro results. Conclusion Concisely, the sustained release niosomal organogel of KT could be an effective alternative to oral dosage forms with less systemic side effect and high drug bioavailability.