In 2004, she took a solo engagement with the Berlin State Opera Ballet and, at the age of 17, became the youngest principal dancer in the history of the Berlin State Ballet, where she performed alongside star dancer Vladimir Malakhov. Since 2005, she has been a permanent guest soloist with the Vienna State Ballet and frequently performs leading roles, mainly in the classical repertoire but also on other major international stages. She performed the dual role of Odette-Odile in the Zurich ballet production of The Swan Lake, which was filmed and released by Bel Air Classiques. In 2011, she debuted as Kitri in Don Quixote at the American Ballet Theatre, where she has performed all the principal roles in the classical ballet repertoire as a principal dancer since 2012. Since 2012, she has been a guest artist with the Bavarian State Ballet, and since 2014, she has been a guest principal dancer with the Berlin State Ballet. Her repertoire includes all the major roles in classical ballets, as well as in neoclassical works choreographed by renowned artists such as Kenneth MacMillan, John Cranko, Mauro Bigonzetti, Jerome Robbins, Maurice Béjart, Roland Petit, Jiří Kylián, Uwe Scholz, Vladimir Malakhov, William Forsythe, and others.

Her awards include a gold medal from the Moscow International Ballet Competition in 2001, first prize at the Vaganova-PRIX ballet competition in St. Petersburg, and the junior prize at the International Ballet Competition in Nagoya in 2002. In 2005, she was nominated for the Benois de la Danse Award for her role as Nikiya in the ballet La Bayadère, and in the same year she received the German Critics' Award. In 2007, critics declared her the best dancer in the country. In 2014, she was honoured with the Benois de la Danse Award for her performances in ABT.

Polina Semionova performs in Kenneth McMillan's Manon at the Slovak National Theatre Ballet alongside Martin ten Kortenaar, the principal dancer of the Berlin State Ballet.