Shepard, a junior transfer from Nebraska, finished with 18 points and 11 rebounds. She was among five starters scoring in double figures for coach Muffet McGraw. Arike Ogunbowale led the Irish with 21 points and became the school's 37th 1,000-point scorer.
"I was really pleased for Jessica coming in for her first game and getting a double-double," McGraw said. "For Arike to reach 1,000 points in the first game of her junior year is an amazing accomplishment."
Marina Mabrey matched Shepard's 18 points, Jackie Young had 16 and graduate student Lili Thompson had 10. Notre Dame led from start to finish against the undersized and overmatched Mountaineers.
Notre Dame's 121 points is the third most in Irish history and most since it scored 120 against Pittsburgh on Jan. 17, 2012. It's the most in a season opener since defeating Liberty 113-35 on Nov. 24, 1989.
Notre Dame, which shot 58.4 percent from the floor, outscored Mount St. Mary's 68-24 in the paint. Thompson had 8 of 24 assists by the Irish, who outrebounded the Mountaineers 50-27.
"We've been struggling to take care of the ball in practice, so I was really happy," McGraw said. "I was disappointed with our defense. I think we can play better and bring more intensity. We have a lot of work to do on the defensive end."
Mount St. Mary's, which shot 40.7 percent, got 12 points from Ashlee White.