Objective To compare different dry eye mouse models induced by benzalkonium chloride solution, scopolamine hydrobromide subcutaneous injection, and a drying environment with and without benzalkonium chloride solution. Methods Fifty SPF C57BL / 6J mice were divided into five groups: mice in the normal control group received no intervention; mice in the scopolamine hydrobromide injection group were injected subcutaneously with scopolamine hydrobromide solution daily; mice in the benzalkonium chloride solution group received benzalkonium chloride eye drops daily; mice in the electric thermostatic drier group were maintained in a controlled dry environment; and mice in the combined benzalkonium chloridesolution / electric thermostatic drier group received benzalkonium chloride and were maintained in a controlled dry environment. Body mass, body temperature, behavioral changes, basic tear secretion-I test ( SIT), break-up time ( BUT), corneal fluorescein staining, and hematoxylin / eosin staining were compared before and after modeling. Apoptosis of corneal and lacrimal tissues was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling. Expression levels of nuclear factor-κB, interleukin-1β, tumor necrosis factor-α, and other inflammatory factors in lacrimal glands were detected by reverse transcription-quantitative polymerase chain reaction. Results After benzalkonium chloride modeling, the SIT and BUT results and body mass were significantly decreased ( P<0. 01) and body temperature, apoptosis, and inflammatory factors were all increased ( P<0. 01) compared with the normal control group. After scopolamine modeling, the SIT and BUT results were significantly reduced (P<0. 01), tension and anxiety were increased, the whole body and hair were dry, and stools were small and dry in the model compared with the normal control group.Field-experiment scores were increased (P<0. 05) and percentage of time spent in the OE% and TE% values in the elevated cross maze experiment were decreased (P<0. 01), and levels of inflammatory factors were increased (P<0. 05). Body mass gain decreased, body temperature increased (P<0. 01), SIT and BUT results were affected (P<0. 01 ), corneal injury was serious, tear secretion was significantly reduced, and inflammatory factors were increased (P<0. 05) in the combined benzalkonium chloride solution and electric thermostatic drier group. All the measured parameters were similar in the drying group compared with the normal control group. Conclusions Eye drops containing benzalkonium chloride, subcutaneous injection of scopolamine, and benzalkonium chloride plus a dry environment can induce dry eye model mice. Exposure to a drying environment alone for 28 days failed to induce a dry eye model, while scopolamine induced systemic xerosis rather than ocular surface symptoms, making it more suitable for establishing a mouse model of electric thermostatic drier. Benzalkonium chloride plus a dry environment produced the most stable and durable model, with typical clinical symptoms of a dry eye surface, plus high operational feasibility and good repeatability, making it an ideal model for teaching, and clinical and scientific research.