She has emphasized an open-ended, interdisciplinary approach in her work, collaborating frequently with Elfriede Jelinek, exploiting live electronics, and incorporating video.

[3] As a high school student, Neuwirth took part in composition workshops with Hans Werner Henze and Gerd Kühr.

[14] Neuwirth has created several full-length music theatre works, including the video opera Lost Highway (2003), based on David Lynch's film; Bählamms Fest (1993/1997), drawing on the work of Leonora Carrington; The Outcast, referencing Herman Melville; and American Lulu, her free adaptation of Alban Berg's Lulu.

Neuwirth's opera of David Lynch's film Lost Highway incorporates both live and pre-recorded audio and visual feeds, alongside other electronics.

Its premiere took place in Graz in 2003, performed by the Klangforum Wien with the electronics realized at the Institut für Elektronische Musik (IEM).

The UK premiere took place at the Young Vic in London in April 2008, in a co-production with the English National Opera, directed by Diane Paulus and conducted by Baldur Brönnimann.

"[17] Stefan Drees remarked:[18]The catastrophic, the plunge into unfamiliar regions with all the attendant consequences, is therefore a fundamental mood of her compositions, winding like a red thread through her works.Usually assigned to the category of contemporary classical music, her works since the late 1980s have sought to transcend the genre restrictions imposed by the music business.

She has drawn from a range of sources for inspiration, including "art, architecture, literature and music, intellectual history, psychology, natural science, and everyday reality".

Neuwirth's works have expanded from the concert hall into public spaces, for example in Talking Houses (1996), a sound installation for shops along the main square of Deutschlandsberg, Austria (created jointly with Hans Hoffer), and in the sound installation ...le temps désechanté ... ou dialogue aux enfers (2005) at the Place Igor Stravinsky in Paris (near the Stravinsky Fountain).

For this latter work, commissioned in 2005 by IRCAM Paris, a motion-capture camera was used to allow electroacoustic sounds to interact with the streams of people moving through the square.

She worked with video artist Tal Rosner to create the interactive installation Disenchanted Island[20] at Centre Pompidou in Paris (2016).

Her works have been performed by the conductors Pierre Boulez, Peter Eötvös, Daniel Harding, Matthias Pintscher, Valerij Gergjev, Susanna Mälkki, François-Xavier Roth and Alan Gilbert, among others.

Numerous soloists, including Hakan Hardenberger, Antoine Tamestit, Thomas Larcher, Jochen Kowalski, Robyn Schulkowsky, Marino Formenti, Claire Chase and Andrew Watts have participated in performances of Neuwirth's works.