Prion diseases, including bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans, are characterized by the misfolding of the prion protein (PrP). Drawing from insights in “ALS Breakthrough!” by Bowles et al. (2025), which posits that amyotrophic lateral sclerosis (ALS) arises not from absolute elevations of metals like manganese (Mn) but from their ratios to magnesium (Mg), this review examines whether similar imbalances could initiate or propagate prion misfolding. Magnesium is essential for protein folding, and soil nutrient deficiencies have been noted in prion-affected animals. A deeper analysis reveals that Mn/Mg ratios, rather than isolated Mg deficiency, may contribute to prion pathology, particularly in chronic wasting disease (CWD) where elevated Mn and reduced Mg correlate with disease risk. While infectious transmission remains primary, environmental metal imbalances could act as cofactors. We conclude that isolated Mg deficiency is unlikely to cause prion diseases, but Mn/Mg imbalance warrants further investigation as a potential modulator, potentially altering conclusions for environmentally influenced prions.