Benzoxazoles and their derivatives have exerted anti-cancer and anti-inflammatory (immunomodulatory) potential due to their anti-proliferative effect on the cells. These molecules are DNA basebioisosteres, therefore, their mechanism of action could be by mimicking the structures of the DNA bases and halting the DNA polymerization processes. Based on their anti-proliferative effect, in our study we aimed to decipher the potential anti-inflammatory activities of unique bisbenzoxazole derivatives in vitro on mammalian macrophages. Being able to manipulate the inflammatory function of macrophages would enable the regulation of the immune response against danger stimuli. This would enable us better prognosis against different types of the diseases ranging from autoimmune disorders to cancer. Our results support the stark anti-inflammatory potential of bisbenzoxazole derivatives RHE 241 and RHE 248 in vitro on the LPS activated mammalian macrophages. After further delineation of their mechanism of action in vitro and their in vivo potency, these molecules could be utilized as potent anti-inflammatory medicines.