The objective of this study was to evaluate the treatment effect of doxycycline, azithromycin and imidocarb on dogs with natural E. canis infection. 98 dogs that tested positive for E. canis were randomly divided into three regimens: regimen 1, 38 dogs, treated with doxycycline; regimen 2, 33 dogs, azithromycin, and regimen 3, 33 dogs, imidocarb. Hematological parameters: white blood cells, red blood cells (RBC), hemoglobin (HGB), hematocrit (HCT), platelet (PLT); blood biochemical parameters: amylase, lipase, aspartate transaminase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), urea and creatinine, blood smear and clinical health status were analyzed within and among regimen(s) on day 0 and day 7, 15, 21, 28, and 60 post-treatment. The results show that RBC, HGB, HCT, and PLT increase gradually through treatment. The biochemical parameters decrease gradually from day 0 to day 28. In regimen 2 and on day 60, amylase, urea, AST, ALT, and GGT rise again. By day 60 post-treatment, 6/38 (15.8%) dogs in regimen 1, 12/27 (44.4%) dogs in regimen 2, and 8/33 (24.2%) dogs in regimen 3 show signs of disease recurrence. The blood smear exam on day 60 shows that 7/38 (18.4%) dogs in regimen 1, 14/27 (51.8%) dogs in regimen 2, and 11/33 (33.3%) dogs in regimen 3 still have E. canis morulae in monocytes and/or neutrophils. In conclusion, doxycycline shows the best effect on treating dogs with natural E. canis infection compared with azithromycin and imidocarb at mentioned dosages and therapeutic duration.