Therapeutic oligonucleotides (ONs) are a new generation of drugs that have captured the attention of the pharmaceutical industry over the past decade, as evidenced by the FDA approval of 14 ONs drugs since 2018. Although therapeutic ONs are complex to analyze, there is an unprecedented need for powerful analytical methods to serve this scope, and liquid chromatography coupled to mass spectrometry (LC-MS) is one of the leading analytical techniques. Ion-pairing reversed-phase liquid chromatography (IP-RPLC) is the gold standard for ON characterization, but hydrophilic interaction chromatography (HILIC) has clearly emerged as an alternative option. This review critically examines recent advances in HILIC-MS analytical developments for the analysis of therapeutic oligonucleotides and their impurities. In particular, the critical selection and optimization of the chromatographic conditions are discussed, together with the latest technological advances required for HILIC-MS coupling. Finally, several applications of HILIC-MS in the context of pharmaceutical analysis and bioanalysis are reported.