[6] In 1999, while still a student, Prestini co-founded VisionIntoArt, an interdisciplinary arts company that established the annual 21c Liederabend festival, which went on to be performed at Disney Hall with the Los Angeles Philharmonic,[7] and at BAM's 2013 Next Wave Festival (in collaboration with Beth Morrison Projects),[8] the Colorado Project (for which the New York Times called her music "downright gorgeous")[9] premiered at Houston's Da Camera Series, The Met Museum, Stanford University and the Kennedy Center, and a variety of other multimedia collaborations.

Her Hubble Cantata was performed in the largest to date communal VR experience at Bric's Celebrate Brooklyn; the New Yorker said of the event "six thousand of us together, in Prospect Park, Brooklyn, [were] floating around the Orion Nebula...Crescendos, beauty, drama…It astounded me, this feeling of floating above Earth, and tears began to emerge from my cardboard goggles..."[10] while Hyperallergic called it "a thundering opus”.

[13] She has been quoted by Timeout NY as "Paola Prestini is a name to know in New York new music, as she works to secure a home for innovative composition and performance in Williamsburg".

[16] Some of the compositions she has written or is working on include Gilgamesh, Laybyrinth, The Hubble Cantata, Aging Magician, Epiphany, The Colorado, Oceanic Verses, Two Oars, and Mass Re-Imaginings.

[18] Of Aging Magician, Anthony Tommasini of the New York Times stated that “[Prestini’s] choral writing is ethereal, unfolding in long-spun lines and chantlike phrases.

[Prestini's] atmospheric but tuneful music for “Gilgamesh” inhabited an indie-opera rainforest of its own…”[19] and The Boston Music Intelligencer said of it “It sparkles, both literally and figuratively…Her melodies entice and speak of a modern, yet accessible flare…it holds its intensity with valor through its end.”[20] Upcoming large scale work include a new installment of the River Project with filmmaker Murat Eyuboglu (filmmaker of the Colorado) based on the Amazon, which currently won a 2017 NEA award,[21] and Two Oars, a new opera with Robert Wilson, and the cellist Jeffrey Zeigler.

Prestini has held residencies at Florida's Hermitage Artist Retreat, LMCC Governor’s Island, MASS MoCA, The Park Avenue Armory, The Watermill Center and Wyoming's Ucross Foundation.