Background: The COVID-19 vaccines have been an essential measure to help reduce COVID-19-related injury and death. However, in some cases, vaccination has caused severe and chronic reactions, akin to post-acute sequelae of COVID-19 (long COVID). Cases: Here we present two cases (Case 1: male, age 43 years, Pfizer BNT162b2 vaccination; Case 2: female, age 30 years, Oxford-AstraZeneca ChAdOx1nCoV-19 vaccination) with severe neurological adverse reaction post-vaccine and concomitant vitamin B12 deficiency. Both cases presented with non-textbook symptomatology of vitamin B12 deficiency. Case 1 had full symptom resolution with vitamin B12 replacement therapy. In Case 2, frank vitamin D deficiency and chronically elevated D-dimer were also found. Case 2 is still undergoing replacement therapy and this manuscript will be updated as appropriate. Discussion: Vaccines, including the COVID-19 vaccines, are known to cause severe and/or chronic neurological reactions in rare cases. We support screening for vitamin B12 deficiency prior to vaccination in high-risk groups (e.g. those following an animal produce free diet), those suffering atypical/chronic vaccine reactions, and those with similar conditions, such as post-acute sequelae of COVID-19 (long COVID). A hypothesis is also presented demonstrating the links between vitamin B12 and vitamin D deficiency and other pathologies (e.g. mast cell activation disorders) that, if validated, could help explain some vaccine hyperreactions.