Quiñones, 62, was approved by a voice vote. Jeffrey L. Schmehl, Berks County president judge, was approved 100-0.
On the Senate floor, Sen. Bob Casey (D, Pa.) said Quiñones was "a great American story," noting that she had been born and educated in Puerto Rico.
Casey said Schmehl has long been "laboring in the vineyards" of the judicial system.
Quiñones and Schmehl "have tremendous experience," Casey said.
President Obama, speaking at a LGBT Pride Month reception at the White House, highlighted the Philadelphia judge's pioneering ascent.
"I want to congratulate Nitza Quiñones Alejandro, who just a few hours ago was confirmed by the Senate, making her the first openly gay Hispanic federal judge in our country's history," Obama said to a cheering audience. "Good news."
Toomey (R., Pa.) said he strongly supported both judges, calling them "both eminently qualified, terrific individuals."
Quiñones earned a bachelor's degree in business administration and a law degree from the University of Puerto Rico.
She worked with Community Legal Services from 1975 to 1977, was an adviser for the U.S. Department of Health and Human Services from 1977 to 1979, and was a staff attorney for what is now the U.S. Department of Veterans Affairs from 1979 to 1991.
Quiñones was nominated by Gov. Robert P. Casey to a vacancy on Common Pleas Court in 1991 and was then elected to full 10-year terms. She was the court's first Latina judge.
Much of her tenure has been as a judge in civil cases, and she is a judicial team leader specializing in complex civil litigation.
Schmehl, 57, of Reading, has been a Berks County judge since 1998 and president judge since 2008.
The Eastern District comprises nine counties: Philadelphia, the four suburban counties, and Lehigh, Northampton, Berks, and Lancaster.
Contact Robert Moran
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Inquirer staff writer Jonathan Tamari contributed to this article.