Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to children. Hence, ALL is still a challenging disease to be cured in adult population. Aberrant genetic alterations have been observed previously in ALL, while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study was attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the relationship between the genomic heterogeneity and prognosis. The results showed the similar common mutation types in two populations but the increased prevalence of genetic alterations in adult ALL. The median number of detected gene mutations was 17 (range: 1–53) per sample in adult ALL and 4.5 (range: 1–19) in pediatric ALL(P<0.001). A significant correlation between the increased number of gene mutations and age was found (R2 = 0.5853, P<0.001). 122 and 53 driver genes were identified in adult and pediatric ALL samples, respectively. The IKZF1, IDH1 and TTN mutations were significantly enriched in adult ALL. The incidence of relapse was 40.0% and 9.6% in the adult and pediatric ALL, respectively(P=0.0003). The overall survival (OS) and relapse free survival (RFS) of adult ALL were poorer than pediatric ALL (P=0.0002, P<0.001, respectively). This genomic landscape enhanced the understanding of the biological differences of ALL between the two populations and provided a clue for novel therapeutic approaches.