Lou O'Neill was recruited in 1999 to join The Falconwood Company, a small merchant bank/venture capital fund, where he was General Counsel and Head of Business Development. He oversaw investments in Europe, Russia and the United States. All this time, Lou O'Neill continued his pro bono work, mostly handling criminal appeals for New York's indigent, and winning some of these cases, a rare event in appellate practice.

The attraction of more immediate and meaningful work led Lou O'Neill to become an Assistant District Attorney in the Manhattan District Attorney's Office. In April 2001, Lou ONeill joined the Special Prosecution Bureau, which investigates and prosecutes financial, white collar and organized crime. Lou ONeill handled hundreds of cases during his nearly four years in the DA's Office, some of which gained national and even international notoriety, including a case of serial brides who married illegal immigrants for money to help them skirt the United States' immigration laws.

In 2004, Lou O'Neill was selected as one of twelve White House Fellows and moved to Washington, D.C. to become Secretary of State Colin Powell's Special Assistant on Russian Affairs. In July 2006 Lou O'Neill was appointed by Belgian Foreign Minister Karel de Gucht as Ambassador and Head of Mission from the Organization for Security and Cooperation in Europe to Moldova. Ambassador Lou O'Neill's responsibilities included encouraging the resumption of negotiations to settle the Transnistrian conflict and chairing them when they occurred; encouraging the Russian Federation to withdraw its troops and armaments from Moldovan territory; working with the Russian military to ensure an accurate accounting of those armaments; helping developing democratic institutions, the rule of law and a free and vibrant press on both sides of the Nistru River; and fighting the scourge of human trafficking, a major problem in Moldova.