The etiology of motor neuron disease (MND) is still unknown. The aims of this study were to: (1) analyze MND mortality at a fine-grained level; and (2) explore associations of MND and heavy metals released into Spanish river basins. MND deaths were extracted from the Spanish nationwide mortality registry (2007–2016). Standardized mortality ratios (SMRs) for MND were estimated at a municipal level. Sites that emitted quantities of heavy metals above the regulatory thresholds were obtained from the European Pollutant Release and Transfer Register database (2007–2015). The relative risks for non-exposed and exposed municipalities (considering a downstream 20 km river section) by type of heavy metal were analyzed using a log-linear model. SMRs were significantly higher in central and northern municipalities. SMRs were 1.14 (1.10–1.17) higher in areas exposed to heavy metals than in non-exposed areas: 0.95 (0.92–0.96). Considering the different metals, we found the following increased MND death risks in exposed areas: 20.9% higher risk for lead, 20.0% for zinc, 16.7% for arsenic, 15.7% for chromium, 15.4% for cadmium, 12.7% for copper, and 12.4% for mercury. This study provides associations between MND death risk and heavy metals in exposed municipalities. Further studies investigating heavy metal exposure are needed to progress in MND understanding.