Antimicrobials are co-administered frequently worldwide in medical as well as veterinary practices. Often, the therapeutic efficiency of two antimicrobial drugs may induce adverse effects. In this study, the possibility of a clindamycin/spectinomycin interaction effect and the efficacy of the combination were investigated in 23 day-old chickens experimentally infected with E. coli. The challenged chickens were orally treated with Clindamycin (11mg/ kg body weight) or spectinomycin (51.1 mg/L) for 5 successive days with a combination of both drugs at therapeutic and half-therapeutic doses. Two blood samples were collected from five chickens of each group on the 4^th day during the treatment course and on the 2^nd, 7^th, 14^th and 21^st days post-treatment. The results revealed that co-administration of clindamycin/spectinomycin reduced the severity of clinical signs and altered the biochemical function parameters related to liver, kidney and of oxidative stress. The effect of both drugs was short-lived, and most of the parameters returned to normal within 2 weeks after administration of them. It is concluded that, the therapeutic doses co- administration of clindamycin/spectinomycin reduced the severity of E. coli infection clinical signs and showed significant alterations in some liver and kidney function parameters as well as oxidative stress. This effect is short-lived and most of the parameters went back to normal within 2 weeks post drug(s) administration.