Objective To investigate the intervention effects of Huanglian Huazhuo capsule on endoplasmic reticulum stress (ERS) of islet β cells with coat proteinⅡ (COP-Ⅱ) dysfunction induced by secretion associated Ras related GTPase 1A (sar-1A) knockout. Methods Mouse islet β cells Min6 were divided into 3 groups:blank group (Min6 cells without any intervention), negative control (NC) group (Min6 cells were transfected with sar-1A-NC-small interfering RNA[siRNA]), and sar-1A siRNA group (Min6 cells were transfected with sar-1A siRNA). Min6 cells transfected with sar-1A siRNA were collected and divided into blank serum group (cells cultured in medium with 10% blank serum), 5%, 10%, and 20% Huanglian Huazhuo capsule groups (cells cultured in medium with 5%, 10%, and 20% serum containing Huanglian Huazhuo capsule), and rosiglitazone group (cells cultured in medium with 10% serum containing rosiglitazone). The expression of sar-1A mRNA in Min6 cells was detected by quantitative polymerase chain reaction, the expression of sec31 protein was detected by immunofluorescence, and the expression of proinsulin, phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), C/EBP homologous protein (CHOP), X-box binding protein 1 (XBP1), inosital-requiring enzyme 1 (IRE1), and X-box proteins was detected by Western blotting. Results There were no significant differences in sar-1A mRNA, sec31, proinsulin, p-eIF2α, CHOP, XBP1, IRE1, or X-box protein between the blank group and the NC group (all P>0.05). Compared with the NC group, the sar-1A siRNA group showed decreased expression of sar-1A mRNA, sec31 protein, proinsulin, and X-box protein (all P<0.05), and increased expression of p-eIF2α, CHOP, XBP1, and IRE1 proteins (all P<0.05). Compared with the blank serum group, the sar-1A mRNA expression in the 5%, 10%, and 20% Huanglian Huazhuo capsule groups and the rosiglitazone group was significantly increased (all P<0.05). The expression of sar-1A mRNA was gradually increased in the 5%, 10%, and 20% Huanglian Huazhuo capsule groups (all P<0.05). There was no significant difference in the expression of sec31, proinsulin, p-eIF2α, CHOP, XBP1, IRE1, or X-box protein between the blank serum group and the 5% Huanglian Huazhuo capsule group (all P>0.05). Compared with the 5% Huanglian Huazhuo capsule group, sec31 protein and proinsulin in Min6 cells of 10%, 20% Huanglian Huazhuo capsule groups and rosiglitazone group were significantly increased (all P<0.05), and p-eIF2α, CHOP, XBP1, IRE1, and X-box proteins were significantly decreased (all P<0.05). Conclusion COP-Ⅱ dysfunction is found in the islet β cells after sar-1A knockdown, and Huanglian Huazhuo capsule can reduce ERS of islet β cells after sar-1A knockdown.