Lefkofsky grew up in a Jewish family In Southfield, Michigan, the son of Bill, a structural Engineer, and Sandy, a school Teacher. He attended Tamarack Camps as a youth and later worked as a staff member. After graduating from Southfield-Lathrup High School in 1987, he attended the University of Michigan and graduated with honors in 1991. He continued on at University of Michigan Law School to receive his Juris Doctor in 1993.
In 1997, Lefkofsky married Elizabeth (née Kramer); they have three children.
In 1999, Lefkofsky and Keywell created an Internet company, Starbelly, that specialized in promotional products. The firm experienced rapid "pre-bubble" growth and was sold to Halo Industries in January 2000, with Lefkofsky joining as chief operating officer. A little more than a year later, the company went bankrupt. Halo and Starbelly faced multiple lawsuits from shareholders, all of which were resolved by 2004.
Lefkofsky then co-founded InnerWorkings in fall 2001. The firm provided print procurement services for mid-sized companies; In August 2006, it had an initial public offering. Lefkofsky was on the board of Directors of the firm until October 2012.
In 2006, Lefkofsky and his wife formed a charitable trust, the Lefkofsky Foundation, for the "purpose of supporting charitable, scientific, and educational organizations and causes around the world". The foundation has a focus on children. The foundation has helped fund more than 50 organizations to date.
In January 2007, Lefkofsky co-founded and provided $1 million in funding for ThePoint.com, an online collective action website started by Andrew Mason. New Enterprise Associates led an early stage investment round in ThePoint. In late 2008, the site changed its name to Groupon.com. In October 2009, Groupon raised $30 million from Accel Partners and New Enterprise Associates. In April 2010, Digital Sky Technology and Battery Ventures invested $135 million in Groupon at a valuation of $1.35 billion. In August 2010, Forbes reported that it was the fastest growing company in history.
In May 2008, Lefkofsky joined the committee to bring the 2016 Summer Olympics to Chicago, Chicago 2016.
In February 2010, Lefkokfsky and Keywell announced a new venture firm called Lightbank to develop new companies in the Chicago area. In December 2010, Google offered a reported $6 billion for Groupon. The offer was turned down, possibly due to anti-trust and regulatory scrutiny the deal might face. In October 2011, Groupon raised $950 million in private funding and then paid $810 million to employees and Investors. Lefkofsky and family were paid $398 million.
In 2013, Lefkofsky and his wife joined The Giving Pledge.