Objective To investigate the role of endoplasmic reticulum protein SEL1L in the maintenance of physiological activities of the central nervous system in mammals. Methods Neuron-specific SEL1L knockout mice (NKO) were generated using the Cre/loxp strategy. Both female and male mice were divided into experimental group (NKO) and wild-type group (WT), with 10 mice in each group and of both sexes. The postnatal survival time, body weight and behavioral indicators such as strength of skeletal muscle, balance coordination, locomotion and anxiety of the mice in each group were compared and analyzed to evaluate the physiological role of SEL1L in the central nervous system. Results The survival time of the NKO mice was only (6±3) weeks on average. Although the neonatal body weight of the NKO mice was similar to that of the wild-type mice, both the male and female NKO mice were significantly more retarded in growth than the wild-type mice, since the body weight of the NKO mice was 54.64%, 40.54% and 38.57% of the WT mice at 3, 5 and 8 weeks of age, respectively. The strength of skeletal muscle of the male NKO mice was 44.24%, 48.09% and 49.04% of male WT mice, and as for the female NKO mice, it was 39.39%, 50.19% and 49.69% of the female WT mice at those three postnatal time points. The movement time, which indicates the balance coordination, of the male NKO mice was 26.92%, 41.58% and 37.48% of the male WT mice, and the movement time of the female NKO mice was 46.02%, 47.67% and 38.48% of the female WT mice. The movement distance in the open field test and the time spent to enter the central region of the male NKO mice were (24.63%, 9.57%), (25.87%, 11.63%) and (51.96%, 9.97%) of the male WT mice, and as for the female NKO mice, those two indicators were (35.62%, 25.93%), (42.75%, 9.77%) and (34.77%, 14.49%) of the female WT mice. In addition, the NKO mice showed more prominent anxiety. There were significant differences between the NKO group and the WT group for all of the experiments above (P < 0.001). Conclusions The data of the postnatal survival time, the body weight and the behavioral indicators such as balance coordination, locomotion and anxiety of the mice show that the condition of the NKO mice is significantly worse than that of the WT mice, indicating an important role of SEL1L in the maintenance of physiological functions of the central nervous system.