To determine whether decreased optic nerve head (ONH) blood flow (BF) precedes or follows decreased circumpapillary retinal nerve fiber layer thickness (cpRNFLT) in eyes with open-angle glaucoma (OAG). Retrospective, longitudinal study. This study followed up 350 eyes of 225 OAG patients for at least 2 years and collected data from each patient from at least 5 examinations obtained with laser speckle flowgraphy (LSFG) and OCT. In the superior, temporal, and inferior ONH quadrants, tissue area mean blur rate (MT), representing ONH tissue BF, was measured with LSFG, whereas cpRNFLT was measured with OCT. A multivariate linear mixed-effects model was used to identify potential predictors of faster MT decrease, adjusting for possible confounding factors. Based on these results, each quadrant of each patient was assigned a risk point if the quadrant was the superior or temporal, if patient age was older than the median (61 years), and if patient pulse rate was higher than median (74 beats per minute). The quadrants were then compared with a mixed-effects Cox model for MT and cpRNFLT changes, defined as a difference between the baseline value and the values from the latest 2 consecutive follow-up visits of more than 1.96 × the corresponding coefficient of variation. Ophthalmic and systemic variables and MT and cpRNFLT in the superior, temporal, and inferior quadrants. The multivariate model showed that MT decrease was faster in older patients with higher pulse rate and slower in inferior quadrants (P < 0.05). Quadrants with 0 risk points showed primary cpRNFLT decrease (P = 0.048), 1-risk point quadrants showed simultaneous cpRNFLT and MT decrease (P = 0.260), and 2-risk point and 3-risk point quadrants showed primary MT decrease (P < 0.001). Older patients with higher pulse rate are at greater risk of a primary reduction in ONH tissue BF, that is, preceding cpRNFLT decrease, in the superior and temporal quadrants.