During his previous diplomatic activity in Bulgaria, he already saved many Bulgarian Jews by issuing them baptismal certificates and safe conducts for the trip to Palestine.
As papal nuncio representing Pope Pius XII in Hungary, Rotta actively protested Hungary's mistreatment of the Jews, and helped persuade Pope Pius XII to lobby the Hungarian leader Admiral Horthy to stop their deportation. According to historian of the Holocaust Martin Gilbert, "With Arrow Cross members killing Jews in the streets of Budapest, Angelo Rotta, the senior Vatican representative in Budapest, took a lead in establishing an "International Ghetto", consisting of several dozen modern apartment buildings to which large numbers of Jews - eventually 25,000 - were brought and to which the Swiss, Swedish, Portuguese, and Spanish legations, as well as the Vatican, affixed their emblems."
Rotta also got permission from the Vatican to begin issuing protective passes to Jewish converts - and was eventually able to distribute more than 15,000 such protective passes, while instructing the drafters of the documents not to examine the recipients' credentials too closely. A Red Cross official asked Rotta for pre-signed blank identity papers, to offer to the sick and needy fleeing the Arrow Cross, and given the documents, and Rotta's blessing. Rotta encouraged Hungarian church leaders to help their "Jewish brothers", and directed Fr Tibor Baranszky to go to the forced marches and distribute letters of immunity to as many Jews as he could.
In 1944 - 1945 Rotta contributed greatly to the saving action of the Neutral Powers (Portugal, Spain, Sweden, Switzerland, the Vatican) and the International Red Cross Committee in Budapest (initiated by Carl Lutz, and led, among others, by Giorgio Perlasca, Friedrich Born, Raoul Wallenberg, Angel Sanz Briz). As the Dean of the Diplomatic Corps, he vehemently protested several times to the Hungarian Governments against the Jewish Deportations.
On 15 November 1944, the Hungarian Government established the "Big Ghetto" for 69,000 Jews, while a further 30,000 with protective documents went to the International Ghetto. On 19 November 1944, the Vatican joined the four other neutral powers - Sweden, Spain, Portugal and Switzerland - in a further collective protest to the Hungarian Government calling for the suspension of deportations of the Jews. The government complied, and banned the "death marches" - but Budapest was by that stage near anarchy, and deportations continued from 21 November. The Arrow Cross continued their orgy of violence, raiding the international Ghetto and murdering Jews, as Soviet forces approached the city. Rotta and Wallenberg were among the few diplomats to remain in Budapest. Following the Soviet conquest of the city, Wallenberg was seized by the Russians and taken to Moscow, from where he was never released. Gilbert wrote that of the hundred and fifty thousand Jews who had been in Budapest when the Germans arrived in March 1944, almost 120,000 survived to liberation - 69,000 from the Big Ghetto, 25,000 in the International Ghetto and a further 25,000 hiding out in Christian homes and religious institutes across the city.
Rotta retired from diplomacy in 1957 and was recognized as Righteous among the Nations by Yad Vashem in 1997.