Extranodal NK/T cell lymphoma (ENKTL) and the pre-malignant chronic active EBV disease (CAEBV) are aggressive conditions arising from the rare infection of T or NK cells by Epstein-Barr virus (EBV). Such conditions have poor patient survival rates due to limited therapeutic options beyond chemoradiation or haematopoietic stem cell transplantation. Assessment of large compound libraries for drug repurposing in ENKTL or CAEBV treatment has not previously been done. Therefore, the therapeutic potential of thousands of compounds remains in part unknown. To uncover these possibilities, a high throughput screen (HTS) of ~4000 experimental and clinically approved compounds was performed in four human cell lines of either ENKTL or CAEBV origin. The HTS pipeline identified 36 compounds consistently potent in all cell lines with IC50 values of < 1µM. Histone deacetylase inhibitors (HDACi) were the most prominent drug class in the shortlist contributing 14 of the 36 compounds. Selected HDACi compounds were validated then investigated for their impact on the intrinsic apoptosis pathway where the general trend observed was downregulation of anti-apoptotic proteins and upregulation of pro-apoptotic proteins. ENKTL and CAEBV cells have been reported to exhibit a primary survival dependency on the anti-apoptotic protein BCL-XL shown by their susceptibility to BCL-XL-specific BH3-mimetics, such as A-1331852. Due to the relative expression changes in the intrinsic apoptosis pathway, HDACi-treatment was hypothesised to enhance susceptibility to such BH3-mimetics. Accordingly, BLISS synergism was observed when ENKTL and CAEBV cells were concurrently treated with HDACi and A-1331852. Sensitivity to A-1331852 was also enhanced when cells were pre-treated with HDACi. Taken together, these data suggest that HDACi drugs, which were identified as the most potent drug class in an unbiased HTS, should be considered for repurposing in the treatment of ENKTL and CAEBV as single agents. Furthermore, HDACi synergise with a BCL-XL-specific BH3-mimetic, showing potential as a therapeutic combination.