Born to a Jewish family, Mikhelson began his career as an Engineer after graduating with a degree in Industrial Civil Engineering from the Samara Institute of Civil Engineering in 1977. He started working as a foreman at a construction and assembling company in the Tyumen area of Siberia. One of his initial projects was work on the Urengoi-Chelyabinsk gas pipeline. In 1985, he was appointed as Chief Engineer of Ryazantruboprovodstroy. In 1987, he became General Director of Kuibishevtruboprovodstroy. In 1991, Kuibishevtruboprovodstroy was one of the first companies to undergo privatization after the dissolution of the Soviet Union.
Mikhelson continued as Managing Director at the company, which has been renamed NOVA, until October 1994. He then became General Director of its holding company, Novafinivest, which later became known as NOVATEK. From 2008 until 2010 Mikhelson was Chairman of the Board of Directors for OAO Stroytransgas and OOO Art Finance. He currently holds the position of Chairman of the Board of Directors of ZAO SIBUR and serves on the Supervisory Board of OAO Russian Regional Development Bank.
Mikhelson often partners with Russian Billionaire Gennady Timchenko on Business and investment projects. They are partners and majority shareholders in Novatek and Sibur. In 2013, Mikhelson and Timchenko sold 12% of Sibur to management partners. Both Mikhelson and Timchenko appear on the Forbes list of billionaires. In 2012, Mikhelson was listed as the second-richest Russian in a number of articles including Bloomberg. Mikhelson and Novatek are the main sponsors of the Russian Football Union.
According to Forbes, his personal fortune was estimated at US$18.2 billion as of 2017.
Mikhelson is the recipient of the Russian Federation’s Order of the Badge of Honor.