Objective To observe the skin protective effect of soothing moisturizing care cream in the treatment of acne with isotretinoin soft capsules. Methods From January 2020 to March 2021, 60 patients with moderate acne admitted to the dermatology clinic of our hospital were selected as the research objects. All patients were treated with isotretinoin soft capsule orally. After 2 weeks of treatment, they were randomly divided into observation group and control group, with 30 cases in each group. The observation group was treated with soothing moisturizing care cream for external use, and the control group was treated with zinc oxide ointment for external use. Both groups continued to receive the same dose of isotretinoin soft capsule for oral treatment. The scores of facial abnormal state and discomfort symptoms, skin attributes and stratum corneum water content were compared between the two groups. The satisfaction and adverse reactions of the observation group were recorded. Results The scores of facial skin abnormal state and subjective discomfort symptoms in the observation group were lower than those in the control group (P<0.05). The facial subjective skin attribute score of the observation group was higher than that of the control group (P<0.05). The scores of objective smoothness, water wettability and flexibility in the observation group were higher than those in the control group (P<0.05). There was no significant difference in objective glossiness between the two groups (P>0.05). The water content of skin stratum corneum in the observation group was higher than that in the control group (P<0.05). The observation group had higher satisfaction with treatment and no adverse reactions occurred. Conclusion Soothing moisturizing care cream can relieve the skin discomfort symptoms such as redness and dryness caused by the treatment of acne with isotretinoin soft capsules, improve the skin condition, and has high safety and patient satisfaction.