Though prescribed as first-line drugs for esophageal squamous cell cancer (ESCC) therapy, the antitumor efficacy of Nab-Paclitaxel (Nab-PTX) is still unsatisfactory owing to the limitation on the dosage and therapy duration of Nab-PTX caused by adverse effects. Inspired by the very essential role of Selenoprotein N (SelN) in mediating the calcium homeostasis and the associated redox homeostasis in cells, herein, in this essay, we screened the inhibition effect of selenium-containing drugs in different forms on ESCC cell line. Investigation on KYSE-150 cells demonstrated that Nab-PTX in combination with low dosage of LNT-SeNPs may synergistically improve its antitumor efficacy on ESCC cells through promoting the cellular apoptosis. Proteomics analysis uncovered the core synergistic mechanism of LNT-SeNPs on Nab-PTX was significantly dependent on the endoplasmic reticulum (ER) stress induced by SelN-mediated Ca-IRE1α, IRE1α(S724)-CHOP-BCL2 axis. SelN knockdown KYSE-150 cell model further confirmed the very indispensable role of SelN in mediating the synergistic effect on Nab-PTX. Moreover, in vivo evaluation on KYSE-150 tumor-bearing mice models also demonstrated the supplementation of LNT-SeNPs with low dosage during the Nab-PTX treatment may synergize the antitumor efficacy and significantly mitigate the adverse reactions or toxicity resulting from a substantial dose of Nab-PTX. Overall, along with the facile accessibility of raw materials, this study reports LNT-SeNPs as a synergistic agent to promote the antitumor efficacy of Nab-PTX, which may be translated as a wide-applicable, efficient and highly safe strategy for clinical treatment of ESCC.