Here, we show that low SAMHD1 expression or degradation/depletion is associated with greater sensitivity to clinically relevant DSB-inducing agents’ doxorubicin and PARP inhibitor in DLBCL cells and that low SAMHD1 expression is associated with improved OS in DLBCL patients independent of other adverse factors, including IPI, and is most significant for those with advanced stage and higher risk. Here, SAMHD1 is linked to diffuse large B-cell lymphoma.