Type 2 diabetes (T2D) and cancers are two major causes of morbidity and mortality worldwide. Nowadays, there is convincing evidence of positive associations between T2D and the incidence or prognosis of a wide spectrum of cancers, for example, breast, colon, liver and pancreas. Many observational studies suggest that certain medications used to treat hyperglycemia (or T2D) may affect cancer cells directly or indirectly. The potential mechanisms of the direct T2D cancer links have been hypothesized to be hyperinsulinemia, hyperglycemia and chronic inflammation; however, the metabolic pathways that lead to T2D and cancers still remain elusive. Plasma-free amino acid (PFAA) profiles have been highlighted in their associations with the risks of developing T2D and cancers in individuals with different ethnic groups and degree of obesity. The alterations of PFAAs might be predominately caused by the metabolic shift resulted from insulin resistance. The underlying mechanisms have not been fully elucidated, in particular whether the amino acids are contributing to these diseases development in a causal manner. This review addresses the molecular and clinical associations between PFAA alterations and both T2D and cancers, and interprets possible mechanisms involved. Revealing these interactions and mechanisms may improve our understanding of the complex pathogenesis of diabetes and cancers and improve their treatment strategies.