While studying at the Collegio Romano in 1839, a letter of Joseph Rosati, Bishop of St. Louis, voicing the appeal of the Flatheads for missionary priests, was read out in the refectory, during the meal, and Mengarini felt moved to volunteer for the work.

[2] On 24 April 1841, Pierre-Jean De Smet, Mengarini, and Nicolas Point, with the lay brothers Specht, Huett, and Classens, and nine other companions, began the long journey by river and overland trail to Fort Hall, Idaho, then a trading post, where they arrived on the feast of the Assumption (15 August) and found a party of Flatheads waiting to conduct them to their final destination.

[6] By offering friendship to the Blackfeet, the priests inadvertently destroyed the trust the Salish tribe placed in them, causing tensions to rise and undermine their efforts.

The missionary work progressed until 1849, when raids by the Blackfeet and the defection and relapse of a large part of the Flathead tribe under a rival claimant for the chieftainship forced the mission to close.

In 1852, on request of Joseph Sadoc Alemany, the Archbishop of San Francisco, for Jesuit workers, he was sent to Santa Clara to help establish the Californian mission that was the nucleus of the present college.

Mengarini was stationed at Santa Clara for the rest of his life, acting for thirty years as treasurer or vice-president, until a stroke of apoplexy and failing sight caused his retirement from active duties.

Mengarini's principal contribution to philology is his Selish or Flathead Grammar: Grammatica linguæ Selicæ – published by the Cromoisy Press (New York, 1861) from the third manuscript copy, the first two, laboriously written out by him, having been lost.