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Obesity and type 2 diabetes mellitus are increasingly recognized as important risk factors for cancer development and progression, including cancers of the digestive system. Indeed, epidemiologic evidence demonstrated that both conditions increase the risk of digestive system cancer incidence and mortality, although with sex-specific and ethnic variations for certain associations with specific types of cancers. While these associations were quite consistent, study design and quality differences, lack of uniform adjustment for confounding factors, heterogeneity and various biases require caution when interpreting the results. The intricate processes by which these two closely related metabolic diseases contribute to carcinogenesis involve increased substrate availability and metabolic dysregulation that create a cellular microenvironment permissive to the activation of multiple signaling pathways that contribute to tumor growth and proliferation. This review thoroughly explores the complex interplay of metabolic and inflammatory mechanisms underlying these processes, including hyperglycemia, insulin resistance, altered insulin‑like growth factor-1 signaling, dysregulated adipokines, hormonal imbalance, gut dysbiosis, chronic inflammation and altered immune response, altered mitochondrial function and oxidative stress, circadian rhythm disruption, altered autophagy. Nevertheless, most mechanistic evidence derives from in vitro systems or non-human animal models which may not fully replicate human pathophysiology and disease, and thus extrapolation to human cancer risk should be made cautiously. Given this complex mechanistic interplay, it is evident that obesity and T2DM-associated metabolic alterations play an important role in carcinogenesis, highlighting the need for targeted prevention strategies in high-risk populations, such as weight management and glycemic control, to mitigate cancer burden.