[1] On 29 September 1992, Pope John Paul named him a member of the Pontifical Council for the Pastoral Care of Migrants and Itinerant People.

[7] On 3 November 1997, Pope John Paul named him General Secretary of the Central Committee for the Great Jubilee of the Year 2000, which has been described as "almost certainly the most complex logistical enterprise in recent Roman memory"[7] and "a carnival such as Rome has not seen since the days of Nero".

He also said that the Vatican was facilitating the return of hundreds of priests who had left the active ministry and married in civil ceremonies, but who were now divorced or widowed and were "sincerely sorry" for having strayed from their vocation.

In 1997 he said a relaxing of the celibacy rule for Latin Church priests would not ease the vocations crisis and would have no theological or pastoral foundation.

[citation needed] Pope John Paul made him Cardinal-Deacon of Dio Padre misericordioso in the consistory of 21 February 2001.

[23] In June 2010, Sepe was under investigation by Perugia's public prosecutor's office for financial corruption in connection with the renovation and sale of some of the Congregation's properties.

[21][25] In March 2018 Sepe forwarded to the Vatican a 1,200-page dossier compiled by Francesco Mangiacapra, a male escort, that purported to identify 40 actively gay Catholic priests.

[27] He formally retired as Archbishop of Naples in 12 December 2020, with the appointment of his successor, Domenico Battaglia, at the time Bishop of Diocese of Cerreto Sannita–Telese–Sant’Agata de’ Goti.