To investigate the clinical effect of cetirizine hydrochloride tablets combined with hyaluronic acid gel and compound glycyrrhizin on allergic skin diseases. Methods A total of 80 patients with allergic skin diseases admitted to our hospital from September 2020 to September 2023 were selected as the research objects. According to different dosage regimens, the patients were divided into control group and study group, with 40 patients in each group. The control group was treated with oral cetirizine hydrochloride tablets, the study group was combined with hyaluronic acid gel and compound glycyrrhizin on the basis of the control group. The therapeutic effect, skin function, immune factor level, safety and quality of life were compared between the two groups. Results The total effective rate of the study group was 95.00%, which was higher than 80.00% of the control group (P <0.05). After treatment, the levels of WCSC, CD3+, CD4+ and CD4+/CD8+ in the study group were higher than those in the control group, and the levels of TEWL and CD8+ were lower than those in the control group (P <0.05). There was no significant difference in the incidence of adverse reactions between the study group and the control group (P >0.05). After treatment, the scores of all dimensions of quality of life in the study group were lower than those in the control group (P <0.05). Conclusion For patients with allergic dermatosis during cetirizine hydrochloride tablets treatment period, the combination of hyaluronic acid gel and compound glycyrrhizin can effectively improve the skin moisturizing ability and the immune level of patients, and then improve the therapeutic effect and quality of life, with higher safety.