Thirteen α-aminophosphonate derivatives with artesunate were synthesized by introducing bioactive α-aminophosphonate combination with artesunate in this work. The reaction were easily carried out at normal pressure, low temperature and without any catalyst. Four strains of microbials, namely Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans, were used for the evaluation of the antimicrobial activities of these target compounds. Experimental results indicated that most of the compounds had good inhibitory effects. Compound 7k showed obvious antimicrobial activities with the MICs of 64 μg/ml against Staphylococcus aureus and 32 μg/ml against Candida albicans. Furthermore, when combined with roxithromycin, the synthesized compounds showed overlapping enhanced activities and proved potential antimicrobial synergists of roxithromycin.