The concentration of oxygen in the brain spontaneously fluctuates, and the distribution of power in these fluctuations has a 1/f-like spectra, where the power present at low frequencies of the power spectrum is orders of magnitude higher than at higher frequencies. Though these oscillations have been interpreted as being driven by neural activity, the origin of these 1/f-like oscillations is not well understood. Here, to gain insight of the origin of the 1/f-like oxygen fluctuations, we investigated the dynamics of tissue oxygenation and neural activity in awake behaving mice. We found that oxygen signal recorded from the cortex of mice had 1/f-like spectra. However, band-limited power in the local field potential did not show corresponding 1/f-like fluctuations. When local neural activity was suppressed, the 1/f-like fluctuations in oxygen concentration persisted. Two-photon measurements of erythrocyte spacing fluctuations and mathematical modeling show that stochastic fluctuations in erythrocyte flow could underlie 1/f-like dynamics in oxygenation. These results suggest that the discrete nature of erythrocytes and their irregular flow, rather than fluctuations in neural activity, could drive 1/f-like fluctuations in tissue oxygenation.