Arizona Federal Court has rejected a lawsuit against Energy Fuels' uranium operation plan near Canyon Mine.
The US Forest Service's decision to allow Energy Fuels to re-open the mine had been challenged by the Havasupai tribe and a coalition of conservation groups.
Opposition groups claimed that re-opening the mine would impact upon tribal cultural values, wildlife and endangered species.
Environmental groups also claimed that the mining operations would increase the risk of toxic uranium mining waste, contaminating the aquifers and streams that sustain the Grand Canyon and Colorado River.
Havasupai chairman Rex Tilousi said: "We are very disappointed with the ruling by Judge Campbell in the Canyon mine case.
"We believe that the National Historic Preservation Act requires the Forest Service to consult with us and the other affiliated tribes before they let the mining company damage Red Butte, one of our most sacred traditional cultural properties."
Initially, the Canyon mining plan had been approved by the Forest Service in 1986, despite a challenge by the Havasupai tribe.
After its closure in 1990, the mine was allowed to re-open in 2012 without a plan update or environmental assessment to reflect the extensive changed circumstances since the original review and approval.
Katie Davis at the Center for Biological Diversity said: "This uranium project could haunt the Grand Canyon region for decades to come.
"Uranium mining leaves a highly toxic legacy that endangers human health, wildlife and the streams and aquifers that feed the Grand Canyon."
Environmental groups cited geologists claiming that uranium mining could deplete and contaminate aquifers that discharge into Grand Canyon and that cleaning them up would be next to impossible.