XPO1 (exportin1) mediates nuclear export of proteins and RNAs and it is frequently overexpressed in cancers. Within this study, we reveal that the orally bioavailable XPO1 inhibitor KPT-330 reduced Mcl-1 protein level, through which it synergized with Bcl-xL inhibitor A-1331852 to induce apoptosis in cancer cells. KPT-330/A-1331852 combination disrupted bindings of Mcl-1 and Bcl-xL to Bax, Bak, and/or Bim, elicited mitochondrial outer membrane permeabilization, and triggered apoptosis. KPT-330 generally mitigated mRNA expression and protein synthesis instead of mRNA nuclear export or protein stability of Mcl-1. KPT-330 inhibited mTORC1/4E-BP1 and Mnk1/eIF4E axes, which disrupted the eIF4F translation initiation complex but was dispensable for Mcl-1 reduction and KPT-330/A-1331852 combination-caused apoptosis. Mature rRNAs are integral aspects of the ribosome that determines protein synthesis ability. KPT-330 impeded nucleolar rRNA processing and reduced total amounts of multiple mature rRNAs. Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL inhibitor resistance upon KPT-330 treatment. KPT-330/A-1331852 combination covered up growth that has been enhanced apoptosis of non-small cell cancer of the lung xenografts. Therefore, we clarify the main reason of apoptosis resistance of cancer cells to XPO1 inhibition and create a potential technique for treating solid tumors.