Metal exposure is an intriguing potential culprit in the cause of sporadic amyotrophic lateral sclerosis (ALS). Lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As) are singled out among the ten chemicals of major public health concern by the World Health Organisation. There are numerous case reports and case-control studies linking those metals to an ALS phenotype. Additionally, some studies have demonstrated higher levels of these metals in the blood, cerebrospinal fluid, urine, or spinal cords of patients with ALS compared to controls. Recently, it has been proposed that the interaction between the metal exposure and an individual’s genetic makeup is required to produce epigenetic changes that ultimately lead to ALS. Thus, the aim of this study was to identify the genes, pathways, interactions and relevant gene-regulators connected to Pb, Hg, Cd, As co-exposure and the development of ALS. In silico approach revealed target genes (Comparative Toxicogenomics Database): GSR, GSTP1, PON1, SOD1, SOD2, SQSTM1, TP53; pathways (Metascape): response to oxidative stress, Detoxification of Reactive Oxygen Species, Fluid shear stress and atherosclerosis, response to lipopolysaccharide, generation of precursor metabolites and energy; Since, it is well known that miRNAs and transcription factors are the key factors involved in regulating gene expression further analysis revealed key miRNAs (MIENTURNET): hsa-miR-325-3p, hsa-miR-1297/hsa-miR-26a-5p/hsa-miR-26b-5p/hsa-miR-4465; and transcription factors (ChIP-X Enrichment Analysis version 3): NFE2L2, ETV7, ZNF888, TRAFD1, NFKB1, DDIT3, ZNF267, MTF1, ZNF581, GLMP. This study elucidates the intricate epigenetic targets and mechanisms associated with metal exposure, emphasizing their potential role in the development of sporadic ALS.