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Down syndrome (DS), or Trisomy 21 (Ts21), is the most common chromosomal survival aneuploidy. Nevertheless, people with DS have compromised health, and the increase in their life expectancy further heightens the risk of developing chronic degenerative diseases such as obesity, dyslipidemias and diabetes mellitus associated with higher morbidity, and mortality for cardiovascular disease from an early age. DS is also accompanied by a higher risk of neurodegeneration. The extra genetic material that characterizes DS causes an imbalance in the genetic dosage, including overexpression of miR-155 and Let-7c miRNAs, both associated with cognitive impairment and dementia in adults. The dynamics of expression of their putative target genes in the early stages of the development of DS and their clinical associations, however, remain to be ascertained. This study aimed to evaluate the relative expression of miR-155 and Let-7c in young and adult individuals with DS and its possible association with biochemical indicators of lipid metabolism. The anthropometric, clinical, biochemical, and gene expression features of miR-155 and Let-7c were analyzed in a population of 52 control and 50 DS subjects divided into groups of 20 years of age or younger and 21 years or older. Expression changes for miR-155 were not significant. Nevertheless, a negative correlation for HDL-Cholesterol concentrations and miR-155 expression was identified. Notably, Let-7c was overexpressed in DS from young and old ages. Overall, our results suggest that Let-7c is related from early stages to cognitive impairment in DS, while a similar role of miR-155 in late stages could be mediated by alterations in lipid metabolism. Further studies with both miRNAs will shed light on their potential as therapeutic targets to prevent or delay cognitive impairment in DS.