Researchers opened a centuries-old Florence tomb on Friday in a search for remains that could confirm the identity of the woman whose enigmatic smile Leonardo da Vinci immortalized in the Mona Lisa, one of the world’s most famous paintings.

A round hole, just big enough for a person to wriggle through, was cut in the stone church floor above the family crypt of Florentine silk merchant Francesco del Giocondo, whose wife, Lisa Gherardini, is thought to have sat for the Renaissance master in the early 16th century....