Cryptosporidium spp. are important emerging pathogens that can cause infections in humans, especially in immunosuppressed patients. Treatment of diseased calves that shed the infectious stage of the protozoon is critically important to prevent contamination by Cryptosporidium spp. oocysts. The objective of this study was to determine if a combination of azithromycin and toltrazuril provides a better treatment option for calf crypto-sporidiosis compared to the use of either agent alone. A total of 55 Holstein calves with cryptosporidiosis were randomly assigned into four groups. Group A (n = 15) received azithromycin at a dose of 20 mg/kg/day per os for six days, group T (n = 15) received toltrazuril at a dose of 20 mg/kg per os every other day on a total of three occasions, and group AT (n = 15) received the combination of both drugs. The control group (n = 10) received purified water. A randomised, placebo-controlled, double-blinded clinical study was designed. The number of oocysts in faeces and clinical parameters were followed daily. Selected haematological and biochemical parameters were measured at the beginning and end of the study. The calves receiving the combination of azithromycin and toltrazuril exhibited a better clinical score as well as the lowest number of oocysts at all time-points. In conclusion, the combination of azithromycin and toltrazuril promotes rapid clinical recovery in calves infected with cryptosporidiosis and stops oocyst shedding. Thus, the combination of azithromycin and toltrazuril is an effective alternative treatment option for calf cryptosporidiosis.