Dams and river regulation greatly alter the downstream environment for gross primary production (GPP) because of changes in water clarity, flow, and temperature regimes. We estimated reach-scale GPP in five locations of the regulated Colorado River in Grand Canyon using an open channel model of dissolved oxygen. Benthic GPP dominates in Grand Canyon due to fast transport times and low pelagic algal biomass. In one location, we used a 738 days time series of GPP to identify the relative contribution of different physical controls of GPP. We developed both linear and semimechanistic time series models that account for unmeasured temporal covariance due to factors such as algal biomass dynamics. GPP varied from 0 g O2 m−2 d−1 to 3.0 g O2 m−2 d−1 with a relatively low annual average of 0.8 g O2 m−2 d−1. Semimechanistic models fit the data better than linear models and demonstrated that variation in turbidity primarily controlled GPP. Lower solar insolation during winter and from cloud cover lowered GPP much further. Hydropeaking lowered GPP but only during turbid conditions. Using the best model and parameter values, the model accurately predicted seasonal estimates of GPP at 3 of 4 upriver sites and outperformed the linear model at all sites; discrepancies were likely from higher algal biomass at upstream sites. This modeling approach can predict how changes in physical controls will affect relative rates of GPP throughout the 385 km segment of the Colorado River in Grand Canyon and can be easily applied to other streams and rivers.