The quagga mussel (Dreissena rostriformis bugensis) is a filter-feeding invasive species that has re-engineered many freshwater ecosystems worldwide. High clearance rates (CRs) and dense populations underpin their ecological impacts. CRs, however, are highly variable, as are environmental factors that regulate them. Despite their widespread distribution in Europe and North America, knowledge of how multiple environmental factors regulate CRs of quagga mussels remains limited. We investigated quagga mussel CRs under varying conditions including water temperature, food availability, habitat depth, flow velocity, and duration of incubation in chambers with both static and flowing water. We found that CR was positively related to water temperature and initial food concentration in static chambers. When coupled with limited food concentration, cold water (7.5 °C), due to a deep-water upwelling event, produced very low CR (~ 10× lower) compared to warmer water (12-24 °C) (0.47 vs. 3.12-5.84 L g-1 DW h-1). Mussels from deeper water (20 m) had CRs that were ~ 3.5× higher than from shallower depths (2-10 m) and CRs were inversely affected by total mussel dry weight. Flow rates from 1 to 22 cm s-1 generated a unimodal pattern of CR with an optimal flow velocity of 6-12 cm s-1 (~ 2× higher than suboptimal CRs). Enhanced flow velocity (22 cm s-1), reflective of storm conditions in shallow waters, significantly increased the closing/reopening activity of mussel valves relative to lower velocities (1-12 cm s-1). Incubation time had a strong negative effect (~ 2-4× reduction) on CRs likely reflecting refiltration in static chambers versus food saturation of mussels in flowing chambers, respectively. Our findings highlight how multiple factors can influence quagga mussel CRs by factors of 2-10. Given widespread habitat heterogeneity in large aquatic ecosystems, whole-lake estimates of mussel impacts should include multiple regulatory factors that affect mussel filtration.