Polyploidization is a major driver of plant genome evolution and speciation. However, most investigations have focused on allopolyploidization, and little is known about the genetic and epigenetic impact imposed by autopolyploidization. In the present study, an autoploidy series (2x, 3x and 4x) in watermelon (Citrullus lanatus) was constructed. The genome structure changes and DNA methylation adjustments at CCGG sites in a genome-wide level were analyzed in the three different autoploidy watermelons by the ISSR, SRAP, and MSAP methods. Compared with diploids, no obvious genetic changes were discovered in autotriploids. Extensive changes occurred in autotetraploids in which sequence eliminations were predominant. However, analysis of DNA methylation level indicated that the total DNA methylation levels were not significantly different between diploid and autotetraploid. Autotriploid showed a trend of low DNA methylation level. It implied that the alterations of DNA methylation levels were not linear with the autopolyploidy level in watermelon. Further analysis suggested that about half of total sites experienced adjustments of DNA methylation patterns in different ploidy watermelons. Interestingly, autotriploid still showed an obvious trend of demethylation. These results indicated some differences from other investigated autopolyploid plants in autopolyploid watermelon. Autotriploid watermelon, in particular, showed unusual characters of genome structure and DNA methylation status, which may be closely associated with the odd-ploidy effect and the excellent traits present in triploid plants.