Most previous research has used an individual water quality parameter, such as calcium, to predict likelihood of zebra mussel establishment in lakes; we employed two multiple-factor methods, our own susceptibility index for zebra mussels in lakes (SIZL) and aragonite saturation state, to evaluate the risk of mussel establishment. Thirty sites in Voyageurs National Park (VNP) were sampled in 2023 for water quality conditions, including those that play a key role in mussel survivability. These results were combined with existing data sets to determine which lakes, and which locations within the larger lakes, are at greatest risk for zebra mussel establishment. Results for VNP indicate that physical lake characteristics and water quality conditions (both single- and multiple-factor methods) put the large, interconnected lakes in VNP at greater risk of zebra mussel establishment than the smaller interior lakes. All sampled interior lakes had alkalinity and calcium concentrations below thresholds conducive to zebra mussel establishment, although Mukooda and O’Leary lakes were identified as the most at-risk interior lakes. The area in the large lakes most at risk was Sullivan Bay in Kabetogama Lake, where water quality conditions were found to be conducive to zebra mussel establishment. Results from this study could be used by resource managers to focus additional inspections, decontaminations, and regulations to protect the most at-risk lakes. These multiple-factor methods may be useful in determining the risk of zebra mussel infestation in other water bodies.