The main objective of the present work is to design aspirin nanoparticles loaded suppositories which will reduce the side effects caused by aspirin suppositories. Aspirin nanoparticles were prepared initially based on ionic-gelation mechanism and lyophilized. The prepared nanoparticles were evaluated, and the results confirmed that Fa9 formulation was the best with greater drug entrapment efficiency. Aspirin suppositories were prepared in order to investigate the best base composition. The prepared suppositories were evaluated and FS1, FS3, FS4, FS8, FS11, and FS12 were proved to be the best base compositions based on dissolution performed. The lyophilized aspirin nanoparticles of Fa9 were used to prepare aspirin nanoparticles loaded suppositories. The in vitro results revealed that Fas11 was the best formulation. The main objective of the present work is to design aspirin nanoparticles loaded suppositories which will reduce the side effects caused by aspirin suppositories. Aspirin nanoparticles were prepared initially based on ionic-gelation mechanism and lyophilized. The prepared nanoparticles were evaluated, and the results confirmed that Fa9 formulation was the best with greater drug entrapment efficiency. Aspirin suppositories were prepared in order to investigate the best base composition. The prepared suppositories were evaluated and FS1, FS3, FS4, FS8, FS11, and FS12 were proved to be the best base compositions. based on dissolution performed. The lyophilized aspirin nanoparticles of Fa9 were used to prepare aspirin nanoparticles loaded suppositories. The in vitro results revealed that Fas11 was the best formulation.