The Pope's secretary of state, Cardinal Tarcisio Bertone, sent a message Monday to Archbishop Thomas Rodi of Mobile, Alabama.
The majority of the deaths from the April 25-28 weather system were in Alabama.
"His Holiness Pope Benedict XVI was saddened to learn of the tragic consequences of the devastating tornado which struck Alabama and neighboring states, and he asks you to express his deep solidarity and pastoral concern to those affected by this natural catastrophe," the papal message stated. "He joins all of you in offering fervent prayers that Almighty God will grant eternal peace to those who have died and consolation and strength to the homeless, injured and suffering.
"Upon the local civil and religious leaders, and upon all engaged in the work of relief and rebuilding, he invokes the divine gifts of wisdom, strength and generous perseverance."
April 27 was the deadliest tornado day in the United States since 1925, when a tornado crossed three states and killed 695 people.