Lourdusamy was born in Kalleri [a] (a village near Gingee in present-day Viluppuram district, Tamil Nadu, India) as the seventh of twelve children of Annamarie (aka Matharasi) and Duraisamy Simeon.

Lourdusamy was the elder brother of priest and theologian D. S. Amalorpavadass, who was killed in an automobile accident while travelling from Mysore to Bangalore.

John XXIII elevated him to the episcopal ranks and appointed him to the See of Bangalore, Pope Paul VI invited him to Rome to serve the Universal Church from 1971.

He resigned as Archbishop of Bangalore on 30 April 1971 and left India to serve in the Curial Congregation for the Evangelization of Peoples in March 1971, Secretary of the S.C. for the Evangelization of Peoples, president of the Pontifical Missionary Work and Vice-Grand chancellor of the Pontifical Urbanian University, 26 February 1973, the university at which he was a student from 1953 to 1956.

Pope John Paul II created Lourdusamy Cardinal-Deacon of Santa Maria delle Grazie alle Fornaci fuori Porta Cavalleggeri in the consistory of 25 May 1985; he is the first Tamil to be raised to the rank of cardinal.

He became Cardinal Protodeacon (the senior Cardinal-Deacon) on 5 April 1993, and served as a special papal legate to the funeral of Mother Teresa on 13 September 1997.

He has also visited 110 countries on all continents in the service of Popes John XXIII, Paul VI, John Paul I, and John Paul II, and received numerous distinctions in appreciation of his work and has been honoured by the Governments of Philippines, Republic of China – Taiwan (The Order of the Brilliant Star, First Class – 13 November 1983), France (Commander of the Légion d'honneur – 29 December 1976), and Germany (Das Grosse Verdienstkreuz mit Stern – 10 October 1977), Liberia (Grand Commander of the Order of the Star of Africa – 3 November 1977), Luxembourg (The "Grand-Croix de l'Ordre Grand-Ducal de la Couronne de Chêne" – 29 June 1988).

Cardinal Lourdusamy was fluent in several languages including Tamil, Latin, English, Italian, French, German, Kannada, Spanish, Portuguese, Dutch and Swedish.

[3] His nephew Vincent and Sr. Vellie Fernandez, Sr. Avis Aguiar who cared for him were with him on his 90th birthday four months earlier, again during his final days in the hospital, and accompanied his mortal remains to Pondicherry, India on 6 June 2014.

Cardinal lay in state at Escande's Hall, Petit Seminaire Higher Secondary School, where thousands paid their final respects round the clock, over two days and nights.. On 9 June 2014, after a mass of repose, celebrated by the Papal Nuncio for India and Nepal Monsignor Salvatore Pennacchio, the Cardinals, Bishops and hundreds of priests, his remains were entombed in front of St. Joseph's Altar inside Immaculate Conception Cathedral, Pondicherry.