Serum orosomucoid1-like protein 3 (ORMDL3) is a membrane protein in the endoplasmic reticulum, known to regulate many important signal transduction processes and autophagy regulation, but it is unclear whether it is involved in the intratumoral microenvironment and cancer drug resistance. Our present study found that silencing ORMDL3 increases the inhibitory effect of sorafenib on the viability and proliferation in HCC cells, and increases the sensitivity of HCC cells to sorafenib. In addition, silencing ORMDL3 can increase ROS levels by inhibiting autophagy, thereby increasing sorafenib-induced apoptosis of HCC cells. Further, our study also found that ORMDL3 silencing inhibits autophagy through the PERK-ATF4-Beclin1 pathway, thus affecting sorafenib sensitivity. The in vivo effects of sorafenib were tested by xenografting using nude mice. It showed that silencing ORMDL3 in HCC cells could increase the inhibitory effect of sorafenib on the growth of tumors. This is the first report to describe the relationships among ORMDL3, autophagy, and sorafenib resistance. This study provides available targets that might have a synergetic effect with sorafenib.