Long noncoding RNAs (lncRNAs) are key players in cancer progression by enabling poorly understood mechanisms. NIHCOLE is a lncRNA induced in hepatocellular carcinoma (HCC) whose expression correlates with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells leads to impaired proliferation. Proteomic analyses show that NIHCOLE interacts with factors in the non-homologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair, including the Ku heterodimer. Additionally, we show by electron microscopy that NIHCOLE can bind Ku, likely through small structural motifs (SM) predicted within NIHCOLE. While several SMs can bind Ku with high affinity, prominent among them is SM3. We show by EMSA that SM3 promotes Ku's multimerization and supports the formation of complexes including other NHEJ factors such as APLF and others. Single-molecule DNA forceps indicate that NIHCOLE or SM3 stabilize the synapsis between DNA ends required prior to ligation. Further, NHEJ reconstitution assays with Ku and XRCC4/Ligase4 show that NIHCOLE or SM3 promote the ligation efficiency of blunt-ended DNA breaks. Using γH2AX-immunofluorescence, GFP reporters and the comet assay as read-outs of DNA damage, we corroborated a defect in DNA-damage repair of NIHCOLE-depleted cells after ionizing radiation. Indeed, the combination of radiation with NIHCOLE depletion results in dramatic HCC cell death. Our results indicate that SM3, within NIHCOLE, contributes to the synapsis and ligation of DSBs by NHEJ conferring an advantageous malignant adaptation. Modulation of SM3 with gene therapy coupled to radio- or chemotherapy could help the development of effective therapies for HCC.