Polyploidization is one of the most crucial pathways in introducing speciation and broadening biodiversity, especially in the Plant Kingdom. Although the majority of studies have focused only on allopolyploid or disomic polyploids, polysomic polyploid species have occurred frequently in higher plants. Due to the occurrence of the capabilities of more copies of alleles in a locus which can have additive dosage effects and/or allelic interactions, polysomic polyploids can lead to unique gene regulations to silence or adjust the expression level to create variations in organ size, metabolic products, and abiotic stress tolerance and biotic stress resistance, etc. This review aims to comprehensively summarize the contemporary understanding and findings concerning the molecular mechanisms of gene expression as well as gene regulation in natural typed and resynthesized polysomic polyploid plants. The review investigates the molecular level of phenomena in polysomic polyploid plants such as 1) typically enlarging organ size and stabilizing meiosis, 2) increasing phytochemical content and metabolic products, 3) enhancing the ability to adapt with biotic and abiotic stress, and 4) changing in gene regulation to silence or adjust the expression levels involve in sequence elimination, methylation, gene suppression, subfunctionalization, neo-functionalization, and transposon activation.