The villa was built in 1922 by count Elia and was thus called Villa Elia at the time. Previously, it was known as Villa di San Valentino because it is perched atop the homonymous hill and it had on its grounds a complex that once belonged to the archeologist Antonio Bosio, author of Roma sotterranea, which was published posthumously, in 1632. Bosio left it as inheritance to Order of Malta. Successive owners are not known.
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In 1945, the villa became the seat of the Embassy of Portugal to the Holy See and took the name Villa Lusa, from Lusitania, an ancient Roman region and province that roughly corresponds to modern-day Portugal.