Objective To investigate acs-20;acs-22 double mutant elegans sensitivity to small molecular compound absorbed through skin penetration, and to provide new model for drug screening. Methods Wild type Caenorhabditis elegans N2 (C. elegans N2) as control, acs-20;acs-22 double mutant elegans was verified by PCR. Both wild type and +acs-20;acs-22 double mutant elegans were soaked in hypotonic solution (double distilled water). The survival rates were recorded at the time of 20, 40, and 60 min to compare the sensitivity of both kinds of elegans to the changes of osmotic pressure. Both elegans were treated with DOX (10 mg/mL and 20 mg/mL) and the survival rates were recorded at the time of 12, 24 and 48 h after treatment. Results PCR results showed that the two relevant genes were successfully mutated in acs-20;acs-22 double mutant elegans compared with the wild type C. elegans N2. And acs-20;acs-22 double mutant elegans was more sensitive to hypotonic solution and DOX treatment. Conclusion Compared to wild type C. elegans N2, acs-20;acs-22 double mutant elegans is more suitable for observing in vivo effect of small molecular compound absorbed through skin penetration, and more appropriate to be used as a new model animal for drug screening.