In the late 1980s he ran the marketing for his family's printing press before going on to trade petroleum products.

Otedola has made several donations to the Michael Otedola University Scholarship Scheme, which was established in 1985 to give underprivileged students in Lagos State access to higher education. In 2005 Zenon donated N200 million to the scheme's fund. Since its inception the scheme has benefited more than 1,000 students.

Otedola was born in Ibadan, the capital of Oyo State, western Nigeria, into the family of the late Sir Michael Otedola, Governor of Lagos State from 1992 to 1993.

In 1994 Otedola established CentreForce Ltd, specialising in Finance, Investments and trading. He is also the owner of Swift Insurance.

In 2003, having identified an opportunity in the fuel Retail market, Otedola secured the Finance to set up Zenon Petroleum and Gas Ltd, a petroleum products marketing and distribution company.

As owner and chairman of Zenon, in 2004 he invested N15 billion in downstream infrastructure development and acquired storage depots at Ibafon, Apapa as well as four cargo vessels, amounting to a combined total storage capacity of 147,000 metric tonnes. The same year he acquired a fleet of 100 DAF fuel-tanker trucks for N1.4 billion.

In 2005 Otedola made a N300 million personal donation to the completion of the National Ecumenical Centre—Nigeria's primary place of Christian worship—in Abuja. In 2007 he was among a group of donors who gave N200 million to the State Security Trust Fund in a drive to reduce crime in Lagos State. Later that year he donated N100 million to the Otedola College of Primary Education in Noforija, Epe. In 2008 he donated N80 million to the Faculty of Agriculture at the University of Port Harcourt.

In January 2006 Otedola was appointed a non-executive Director of Transnational Corporation of Nigeria Plc, a multi-sectoral conglomerate established in 2004 by then-President Obasanjo to respond to market opportunities requiring heavy capital investment in Nigeria and across sub-Saharan Africa. He held this post until February 2011.

Otedola has made a number of real estate Investments, including a N2.3 billion acquisition in February 2007 by Zenon of Stallion House in Victoria Island in Lagos, from the Federal Government. The following month he was appointed chairman of the Transcorp Hilton Hotel in Abuja and tasked with driving its expansion and upgrade to a seven star facility. He is the owner of FO Properties Ltd. Otedola has been reported to be a major financier of the People's Democratic Party and is said to have contributed N100 million to President Obasanjo's re-election expenses in 2003. He was a close ally of President Goodluck Jonathan. He has served as a member of the Nigerian Investment Promotion Council (NIPC) since 2004, and the same year was appointed to a committee tasked with developing commercial relations with South Africa. In 2011 Femi Otedola was appointed by President Goodluck Jonathan to Nigeria's National Economic Management Team.

Following Otedola's entry into the company African Petroleum's share price rose sharply, increasing the market capitalisation from N36 billion to N217 billion in six months. In 2008, in response to public concerns over the availability and pricing of Kerosene, African Petroleum launched an initiative to saturate the market and sell the fuel at N50 per litre from more than 500 Service stations across Nigeria.

In March 2009 Otedola became the second Nigerian after Aliko Dangote to appear on the Forbes list of dollar-denominated billionaires, with an estimated net worth of $1.2 billion. In October 2009 Otedola announced a move to upgrade African Petroleum's liquefied petroleum gas (LPG) storage terminals in Lagos, Kano and Port Harcourt. Difficult economic conditions caused by the slump in world oil prices and credit squeeze of 2008–09 led African Petroleum to record a loss in 2009.

In December 2010 African Petroleum rebranded, changing its name to Forte Oil PLC. Otedola carried out a restructuring of the Business, focusing on Technology and improved corporate governance. Forte Oil returned to profit in 2012.

In 2012 Zenon was among a number of companies named in a report into an alleged fuel subsidy scam. According to the report Zenon owed the government $1.4 million. It was further reported that Farouk Lawan, the Nigerian legislator who compiled the report, had apparently been filmed collecting $500,000 of a supposed total sum of $3 million from Femi Otedola to remove Zenon from the list. It subsequently emerged that Otedola had previously reported Lawan's harassment and demands for bribes to the State Security Services, who had orchestrated a sting operation. Lawan was charged with corruption in February 2013.

Otedola is married to Nana Otedola and has three daughters – Christine Olawunmi, Florence Ifeoluwa and Elizabeth Temi—and a son, Fewa. Florence Otedola, aka DJ Cuppy, is a DJ and music Producer, as well as a tourism ambassador for Nigeria. Her younger sister, Temi, is a style Blogger and aspiring designer. Otedola has homes in Lagos, Abuja, Dubai, London and New York City.

In September 2015 Forte Oil sold 17 per cent of its equity to Swiss commodity trader Mercuria Energy Group, giving Forte access to global commodity markets. The deal was thought to have given Otedola an estimated $200 million.

In December 2016, Otedola was embroiled in a controversy where two Toronto-based sisters—Jyoti and Kiran Matharoo—reportedly tried to extort him by cyberbullying and blackmail, claiming they had evidence of Otedola cheating on his wife that they would post on a notorious sex-scandal website.