DNA double-strand breaks (DSBs) are highly cytotoxic lesions that – if misrepaired – can lead to genomic instability, cancer, and developmental disorders. While ubiquitin and select ubiquitin-like proteins (UBLs) are established regulators of DSB repair, many UBLs remain understudied. Here, through systematic UBL screening, we identify UFM1 as a novel regulator of non-homologous end-joining (NHEJ). Using a photo-crosslinkable UFM1 probe, we uncover core NHEJ components, including XRCC4, as downstream UFM1 receptors. Complementary proximity screening reveals UFMylated Ku70 as a key upstream target recognised by XRCC4. Mechanistically, UFMylation facilitates chromatin recruitment and assembly of NHEJ factors, establishing a central role in end-joining repair. Our findings link hereditary UFMylation disorders to defective NHEJ processes, contributing to our molecular understanding of diseases biology. Beyond this, our bottom-up screening strategy reveals broader networks of UFM1-regulated factors, featuring diverse roles in genome maintenance and cellular homeostasis.