After various humanitarian experiences in the field of Non-Governmental Organizations, in 2008 he was appointed president of UNICEF Italia, a position he held until 2011.

On 12 June he was appointed Undersecretary for the Presidency of the Council of Ministers with responsibility for equal opportunities and young people in the first government of Giuseppe Conte.

In July 2019, he was involved in the approval of the Italia bill named "Codice Rosso" which enforced guilties for the crimes of stalking and sexual violence, forbid forced marriages and also introduced the penal prosecution for the revenge porn and female facial injuries.

[9] After Conte's resignation in September 2019, the national board of the Democratic Party (PD) officially opened to the possibility of forming a new cabinet in a coalition with the M5S,[10] based on pro-Europeanism, green economy, sustainable development, fight against economic inequality and a new immigration policy.

On 13 February, Mario Draghi became the new prime minister at the head of a national unity government, but Spadafora was not confirmed in the cabinet.