Many compounds have a limited ability to penetrate into the central nervous system (CNS) due to the existence of the blood-brain barrier (BBB). The CNS distribution of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and diclofenac is of interest because is an effective therapeutic agent for the treatment of neurodegenerative disease in which the long-term use of NSAIDs may reduce the risk, or delay the onset of Alzheimer's disease (AD). The aim of this study was to evaluate the brain-targeting efficiency of two prodrugs of NSAIDs, hydroxyethyl ibuprofen (HEI) and hydroxyethyl diclofenac (HED) after intraperitoneal (IP) administration to rats using the pharmacokinetic analysis in plasma and brain. In vitro stabilities of the two prodrugs were evaluated to determine both their stability in the aqueous medium, and their feasibility to undergo enzymatic cleavage by esterases in biosample, also in vivo study was performed on rats for pharmacokinetic studies. The concentration of the compounds in biosamples including plasma and brain were measured using High performance liquid chromatography (HPLC). The mobile phase that used for diclofenac and HED was consisted of80% methanol, 20% water, to each litre, 2ml acetic acid was added. While the mobile phase for ibuprofen and HEI composed of 20mMphosphate buffer solution(pH2.5) and acetonitrile in volume ratios of 55:45 and 56:54 for plasma and brain sample respectively the pH for the entire mobile phase was 5. The result showed that the AUC brain/AUC plasma ratio was 0.16, 0.16, 1.234, 0.027 for ibuprofen, HEI, HED, and diclofenac respectively. The HED exhibited enhancement of brain targeting as prodrug where its ratio is 45 fold than diclofenac. The ratio for HEI and ibuprofen is the highest but at the same time it is equal to each other, despite that the AUC plasma of ibuprofen is twice more than for HEI, whereas the ibuprofen level in brain and plasma are highly correlated to each other, this is may be explained that the rate of absorption of ibuprofen resulted from IP administration of HEI to the brain is more than the other and the Tmax is very shorter 2.472. In conclusion, the hydroxyethyl-related structure may play an important role in transport across the BBB.