Previously, we showed that the downregulation of both HSP27 and TGF-β1 decreased the survival of various tumor types. However, we found that HSP27/TGF-β1 downregulation was less effective in acquired sorafenib-resistant HCC cell lines. As an alternative to HSP27/TGF-β1 downregulation to induce acute cell death in sorafenib-resistant cancer, we substituted shGRP78 for shHSP27 as a complement to shTGF-β1. The combination of shTGF-β1/shGRP78 was shown to overcome sorafenib resistance in HCC cell lines. Notably, both GRP78 and CD44 accumulate at the cell surface during sorafenib treatment and are accompanied by IRE1α activation; this effect is responsible for triggering and maintaining sorafenib resistance. These results revealed that sorafenib-induced acquired resistance in cancer cells is the result of receptor tyrosine kinase (RTK) feedback activation via the CD44-linked GRP78 signaling pathway with efficient rewiring of the GRP78-IGF1R-PI3K-Akt signaling cascade, which provides strong survival potential as well as a continuous positive feedback loop, resulting in sustained strong sorafenib resistance. In summary, CD44-GRP78 functions as both a sensor of sorafenib-induced ER stress and a mediator of sorafenib resistance.