In the late 1970s, Mashkov entered the biological faculty of Novosibirsk State University, but studied there for only a year, after which he entered the Novosibirsk Theater School, from which in 1984 he was expelled because of improper behavior.

In the movie Mashkov made his debut in 1989 in the movie Green Goat Fire. Then came the roles in the movies Do It — One! (1990), Ha-bi-Assi (1990), Casus improvisus (1991), Love on the Isle of Death (1991), Alaska, Sir! (1992), Me Ivan, You Abraham (1993).

Since 1990 he joined the troupe of the Oleg Tabakov Theater. He played in productions "The Sailor's Silence" (Abram Schwartz), "The Inspector General" (The Governor), "The Myth of Don Juan" (Don Juan), "The Mechanical Piano" (Platonov), "Anecdotes" (Ivanovich, Ugarov).

Since 1992, Mashkov has also become one of the Directors of the Tabakov Theater. He staged there performances "Star Time on Local Time" (1992), "Passion for Bumbarash" (1992), "Death Room" (1994).

However, in 1994 he was best known for his starring roles in Denis Yevstigneev's Limit and Valery Todorovsky's Moscow Nights films. In 1995 Mashkov also played the main role in Karen Shakhnazarov's melodrama American Daughter. One of the most notable works of this period was the role of Tolyan in the picture The Thief (1997), subsequently nominated for an Oscar. In 2000, he played the role of Emelian Pugachev in the historical film of Alexander Proshkin Russian rebellion.

In the Theater "Satyricon" staged the play "The Threepenny Opera" (1996), in the Moscow Art Theater named after A.P. Chekhov - "No. 13" (2001).

In 1997, Vladimir Mashkov made his debut as a filmmaker with the New Year's romantic comedy The Orphan of Kazan. In 2004 he appeared in the role of Director, Screenwriter and Producer of the film Daddy based on the play by Alexander Galich "The Sailor's Silence", in which he also starred Abram Schwartz.

In the early 2000s, Vladimir Mashkov starred in several Hollywood films: Dancing at the Blue Iguana (2000), 15 Minutes (2001), An American Rhapsody (2001), Behind Enemy Lines (2001) ).

Mashkov played the Russian millionaire Platon Makovsky, whose prototype was Boris Berezovsky, in the 2002 drama of Pavel Lungin Tycoon. Next year he appeared on television as a merchant Rogozhin in the adaptation of Fyodor Dostoyevsky's novel The Idiot, directed by Vladimir Bortko.

He starred in the 2005 adaptation of Boris Akunin's novel The State Counsellor, next year he played in the action movie Piranha and the American television series Alias.

In 2007, Vladimir Mashkov played detective David Gozman in the historical crime series Liquidation

He portrayed the character of a hired killer in the 2008 film The Ghost. His next films were the role of the second pilot Seryoga in the action film based on real events Kandagar (2009) and the image of the machinist Ignat in the drama of Alexei Uchitel The Edge (2010). In 2011, Vladimir Mashkov appeared in the American blockbuster Mission: Impossible – Ghost Protocol, where he played Russian agent Sidorov.

In 2011, at the festival of children's amateur theaters in the Siberian region of dolls "Doll in children's hands" in Novokuznetsk, Mashkov announced the establishment of the "Golden Lion" prize named after Natalya Nikiforova (his mother). This nominal premium actor will serve for the year for Best Actor and Best Actress. The first award went to theater Actress Galina Romanova, named Honored Artist of Russia.

In 2015 the thriller TV series Rodina aired on television, directed by Pavel Lungin. Mashkov played officer Alexei Bragin, released from a long imprisonment, who appears to have defected.

The disaster film Flight Crew by Nikolai Lebedev premiered in 2016, where Mashkov played experienced pilot Zinchenko.

In 2017, the Sports drama Going Vertical was released. In this film, Vladimir Mashkov starred in the role of coach of the Soviet basketball team, which at the 1972 Munich Olympics beat the seemingly invincible US team.

He was appointed as artistic Director of the Oleg Tabakov Theatre in 2018.