The urgent need to fight the COVID-19 pandemic has impressively stimulated the efforts of the international scientific community, providing an extraordinary wealth of studies. Improving the current laboratory testing methods and developing new rapid and reliable diagnostic approaches might be useful in managing contact tracing in the fight against both the original SARS-CoV-2 strain and the new, potentially fast-spreading CoV-2 variants. Mass Spectrometry (MS)-based testing methods and more specifically MALDI-MS have demonstrated without any doubt the great potential to overcome many unresolved analytical challenges arising from currently used laboratory testing assays, becoming an effective proteomic tool in several applications, including pathogen identification. With the aim of highlighting the challenges and opportunities that derive from MALDI-based approaches for the detection of SARS-CoV-2 and its variants, we extensively examined the most promising proofs of concept for MALDI studies related to the COVID-19 outbreak.