Originally trained as a pianist, Armstrong graduated with a Bachelor of Music degree from Concordia College in 1963. She later studied with Lotte Lehmann in Santa Barbara, California. She made her operatic debut in 1965 with a secondary company in San Francisco, as Musetta in La bohème. She made her first appearance with the San Francisco Spring Opera the following year, as Elvira in L'italiana in Algeri.
In 1966, Armstrong won the Metropolitan Opera National Council Auditions, which led to her being engaged by the house for small roles. She made her debut at the Met on October 2, 1966, as one of the servants in Die Frau ohne Schatten, under Karl Böhm, with Leonie Rysanek and Christa Ludwig. She continued to perform regularly at the Met through the spring of 1969, in roles like the Paggio in Rigoletto (opposite Cornell MacNeil), Annina in La traviata (with Virginia Zeani), and the Dew Fairy in Hänsel und Gretel (with Teresa Stratas as Gretel).
Preferable contracts emanated from the New York City Opera, and she made her first appearance with that company as the Reine de Chémakhâ in Le coq d'or (with Michael Devlin), in 1969. She was to appear at that theatre many times through 1977, singing such roles as Conceptión in L'heure espagnol (with Kenneth Riegel), Blondchen in Die Entführung aus dem Serail (opposite Patricia Brooks, then Beverly Sills), Violetta Valéry in La traviata, the title heroine in La belle Hélène, and Minnie in La fanciulla del West, among others.
In 1974, Armstrong first appeared in Europe, as Micaëla in Carmen, at the Opéra du Rhin in Strasbourg. The following year, she created a great sensation with her performance of Salome at the same theatre. Further performances in Europe followed, including Tosca in Venice, and Elsa von Brabant in the 1979 Bayreuth Festival's Lohengrin (with Peter Hofmann), directed by her future husband, Götz Friedrich, which was later recorded and filmed. She also sang in Berlin (where she was to be a great favorite), Vienna, Paris, Covent Garden (Lulu, which Robert Craft once declared was "accurately sung and perfectly enacted"), Los Angeles, and the Bolshoi.
Armstrong has sung in several operatic world premieres, including Gottfried von Einem's Jesu Hochzeit (as Death), Giuseppe Sinopoli's Lou Salomé, Luciano Berio's Un re in ascolto, York Höller's Maître et Marguerite and Siegfried Matthus's Desdemona und ihre Schwestern. Other celebrated roles include those in Susannah, Salome, Les contes d'Hoffmann (as Giulietta, opposite Norman Treigle), La voix humaine, Lohengrin, Pelléas et Mélisande, Lulu, Wozzeck, Der Rosenkavalier, Die tote Stadt, Parsifal, Erwartung, Die Walküre (as Sieglinde), Katya Kabanova, The Makropulos Case, Fidelio, Mathis der Maler (as Ursula), Tannhäuser (as Venus, with René Kollo) and Dialogues des Carmélites (as Mother Marie of the Incarnation).
In 1985, Armstrong was named a Kammersängerin in Stuttgart; in 1994, she received the title in Berlin.
Recent roles have included the Widow Begbick in Aufstieg und Fall der Stadt Mahagonny, in Erfurt; Mme Larine in Eugene Onegin, at the Deutsche Oper Berlin (in the Friedrich production); the Old Lady in Candide, at the Flanders Opera; the Queen of Hearts in Unsunk Chin`s Alice in Wonderland in Geneva, and Cecily 'Cissy' Robson in Sir Ronald Harwood's Quartet in Berlin.
- Wagner: Lohengrin (Hofmann; Nelsson, 1982) [live] CBS
- Menotti: Songs (Francesch, 1983) Etcetera
- Berio: Un re in ascolto (Adam; Maazel, 1984) [live] col legno
- Henze: The Bassarids (Riegel; Albrecht, 1986) koch schwann
- Landowski: Montségur (G.Quilico; Plasson, 1987) [live] Cybelia
- Zemlinsky: Lyric Symphony (Kusnjer; Gregor, 1987–88) Supraphon
- Verdi: Falstaff (Bacquier, Stilwell; Solti, Friedrich, 1978–79) Deutsche Grammophon
- Wagner: Lohengrin (Hofmann; Nelsson, Friedrich, 1982) [live] EuroArts
- Korngold: Die tote Stadt (King; Hollreiser, Friedrich, 1983) [live] Arthaus Musik
- "Richard-Wagner-Abend" [includes Wesendonck-Lieder and Liebestod] (Adam; Masur, 1988) [live] Kultur
- Armstrong&psearchtype= San Francisco Opera Archives, sfopera.com; accessed July 29, 2015.
- Profile, metoperafamily.org; accessed July 29, 2015.
- An Improbable Life, by Robert Craft, Vanderbilt University Press, 2002
- "Gotz Friedrich, 70, Longtime Chief Of Prestigious Berlin Opera House". The New York Times. December 15, 2000. Retrieved 2008-03-25.
- The Metropolitan Opera Encyclopedia, edited by David Hamilton, Simon and Schuster, 1987. ISBN 0-671-61732-X
- Karan Armstrong: Das Mädchen aus dem goldenen Westen, by Ruth Renée Reif, Langen Müller, 1996. ISBN 3-7844-2563-1