A year after his Cliburn Competition victory, in 1967, Lupu won the first prize in the George Enescu International Piano Competition. Two years later, in October 1969, he won the Leeds International Piano Competition; he performed Beethoven's Piano Concerto No. 3 (Op. 37) in the Finals. The following month, in November 1969, Lupu played his first solo concert in London; Joan Chissell of "The Times" wrote about his performance of Beethoven's Piano Sonata No. 7 at the recital: "He brought what seemed like a lifetime's experience to its alternating desolation and pride. Never could music come nearer to speech."
In March and April 1970, Lupu made his first recording for Decca Records of Brahms' Rhapsody in B minor (Op. 79 No. 1) and Three Intermezzi (Op. 117), as well as Schubert's Piano Sonata in A minor (D. 784). He has remained an exclusive Decca artist, and continued to record for the label for the following 23 years. In August 1970, the 24-year-old pianist made his debut at The Proms, performing Brahms' Piano Concerto No. 1 (Op. 15) with the BBC Symphony Orchestra conducted by Edo de Waart at the Royal Albert Hall. In November 1970, he made his first concerto recording for Decca, of the Beethoven Piano Concerto No. 3 with the London Symphony Orchestra conducted by Lawrence Foster; he also recorded Beethoven's 32 Variations in C minor (WoO 80).
Lupu's first major concerts in the United States after his Leeds Competition victory were in February 1972 with the Cleveland Orchestra, in the Brahms Piano Concerto No. 1 with Daniel Barenboim conducting at Carnegie Hall in New York City, and in October 1972 with the Chicago Symphony Orchestra, in the Beethoven Piano Concerto No. 3 with Carlo Maria Giulini conducting. The performance of the Brahms with the Cleveland Orchestra and Barenboim was reviewed by Harold C. Schonberg, a Pulitzer Prize-winning music critic for "The New York Times" who had ten years prior notably lambasted the famous New York Philharmonic concert of April 6, 1962 where the same concerto was played by Glenn Gould with the New York Philharmonic conducted by Leonard Bernstein. Schonberg was also critical of the performance by Lupu and Barenboim, writing that not since the Bernstein-Gould performance "had there been such an interpretation" of the concerto, describing it as "willful, episodic and mannered, self-indulgent, capricious". However, he added that "yet through all the eccentricities came the feeling of two young musicians trying hard to get out of the rut and once in a while actually succeeding", but that "in future years this kind of approach may jell for them. Right now it does not come off."
Although Schonberg had been critical of Lupu's debut with the Cleveland Orchestra conducted by Barenboim in February 1972, he was far more enthusiastic of Lupu's performance in November 1972 of Beethoven's Piano Concerto No. 5 with the Royal Philharmonic Orchestra conducted by Lawrence Foster at Carnegie Hall, writing, in "The New York Times", that "his performance did much to redeem the impression he had made last season in the Brahms D minor Concerto. Then he sounded mannered, finicky, artificial. This time he was a different pianist." Schonberg added:The following year, Lupu recorded the piano concertos of Schumann (Op. 54) and Grieg (Op. 16) with the London Symphony Orchestra conducted by André Previn, a recording described by "Gramophone" as "grandly commanding". In February 1974, Lupu performed a recital at Hunter College in New York, which was raved by John Rockwell of "The New York Times". Rockwell declared Lupu "no ordinary pianist" and wrote about Lupu's performance of Schubert's Piano Sonata in B-flat major (D. 960):In November 1974, Lupu made his debut with the New York Philharmonic, performing Mozart's Piano Concerto No. 21 (K. 467) conducted by James Conlon. In 1975, Lupu debuted with the Royal Concertgebouw Orchestra and gave the premiere of the André Tchaikowsky Piano Concerto, Op. 4 with the Royal Philharmonic Orchestra conducted by Uri Segal at the Royal Festival Hall. In 1976, Lupu recorded Brahms' 6 Klavierstücke (Op. 118) and 4 Klavierstücke (Op. 119), which was described by "Stereo Review" as "a glowing realization of what Brahms set down that leaves one at a loss for words and simply glad to have ears." In 1978, he gave his debut with the Berlin Philharmonic conducted by Herbert von Karajan at that year's Salzburg Festival. Reviewing a recital Lupu gave at Avery Fisher Hall in 1980, Andrew Porter of The New Yorker hailed Lupu as "a master of the most satisfying kind". By 1981 he had played with every major orchestra.
In June 1982, Lupu made a critically acclaimed recording of Schubert's Impromptus (D. 899 & 935). John Rockwell wrote in "The New York Times" that Lupu's "singing tone here must be heard to be believed. Without belittling the other facets of Schubert's musical personality, he captures the composer's songful essence with a rare beauty - and, in so doing, he reaffirms once more the ability of present-day performers to do ample justice to the music of the past." In addition, "Gramophone" said about the recording:In 1989, Lupu was awarded the "Abbiati" prize by the Italian Critics' Association. In 1995, he won an Edison Award for his album of Schumann's "Kinderszenen" (Op. 15), "Kreisleriana" (Op. 16) and "Humoreske" (Op. 20) which was also nominated for a Grammy Award. In the Grammy Awards of 1996, he won a Grammy Award for Best Instrumental Soloist Performance (without orchestra) for Schubert's Piano Sonatas in B-flat major (D. 960) and A major (D. 664).
In 2006, Lupu was awarded the Premio Internazionale Arturo Benedetti Michelangeli and in 2016 was appointed Commander of the Order of the British Empire (CBE) in the 2016 New Year Honours for services to music.
Lupu uses a regular, straight-backed chair at the piano as opposed to a standard piano bench. He told "Clavier" in 1981 that while sitting on a bench he tended to lean forward, raise his shoulders, become impossibly stiff and develop pains all over. He also said that he practiced with a chair at home and found it natural for him. Although Lupu is an admirer of the pianism of Arthur Rubinstein and Vladimir Horowitz, he named Mieczysław Horszowski as having the most influence on his playing, saying that Horszowski "speaks to me like no one else". Lupu's initial approach to new music is to read it away from the piano, saying that he "reads more easily away from the instrument" and that "it is the only way to learn". Lupu says in regards to tone production that "everything in music comes from the head', adding: "If you have any concept of sound, you hear it in your inner ear. All you have to work for is to match that sound on the instrument. The whole balance, the line, the tone, is perceived and controlled by the head." He further describes tone production as a "matching process for which [one] practices", and the physical contact of the keyboard as "a very individual thing determined by the color or timbre you hear and try to get, the piece you are playing, the phrase".