<p>Exosomes are released by cancer cells to transport nucleic acids, proteins and lipids to neighboring or distant cells. They participate in various biological processes that promote tumor progression, including uncontrolled proliferation, angiogenesis, migration, local invasion, metastasis, immune evasion and treatment resistance. Experimental studies have reported that tumor acidity enhances the release of exosomes from cancer cells. In this study, we propose a novel mathematical model to investigate the interplay between tumor acidity and exosome secretion under in vivo and in vitro conditions. The model consists of a coupled system of reaction–diffusion equations describing the dynamics of oxygen, lactate, and exosomes, which we solve numerically using the finite difference method (FDM). Our predicted results show strong qualitative agreement with experimental observations. The simulations reveal that exosome levels are higher under oxygen-deprived conditions compared to oxygen-rich conditions. Moreover, in cyclic hypoxia–where oxygen levels fluctuate between normoxic and hypoxic states–lactate accumulation increases with longer hypoxia periods, whereas exosome levels rise under rapid oxygen fluctuations. Additionally, lactate levels reach a steady-state value in spatially heterogeneous oxygen environments. The results also highlight that the oxygen consumption rate has a range in which it is positively correlated with exosome levels.</p>