He was made a cardinal by Pope Benedict XVI in 2006 and has been outspoken on issues regarding human rights, political freedom, and religious liberty.

Zen fled to Hong Kong from Shanghai to escape Communist rule at the end of the Chinese Civil War.

After 1973, he taught in the Holy Spirit Seminary College of Hong Kong – 1976 to 1978 of Macao Salesian School (Instituto Salesiano) as principal.

Democratic Party ex-chairman Martin Lee, also a Roman Catholic, stated that because Zen was still healthy for his age, the Pope may request him to stay in his position.

Legislative Council member Audrey Eu praised Zen for being braver than other religious leaders in Hong Kong in sharing his political views and also because "he carried out his ideas of fairness, equitableness, and philanthropy via actual efforts".

On 15 April 2009, Pope Benedict accepted Cardinal Zen's resignation and John Tong Hon became the bishop of the diocese.

[8] From 22 October 2011 for three days Cardinal Zen went on hunger strike which was undertaken as an act of protest against losing a long-standing legal battle with the Hong Kong government over how aided schools should be run.

Zen, who was created Cardinal-Priest of Santa Maria Madre del Redentore a Tor Bella Monaca, saw his elevation as indication of how much the Pope values the Church in China.

Democrat legislator Martin Lee added that it was good news because no matter whether he is a bishop or a cardinal, as a religious leader Zen speaks as moral voice of the people.

He believes in diplomacy, not in our faith.”[16][17] In 2019, Zen responded to Cardinal Filoni's weeklong trip to Hong Kong, Taiwan, and Macau.

Is information on recent oppression measures missing from our superiors in the Vatican?”[18] Zen later expressed a desire to tell Pope Francis that the pontiff's actions were "encouraging a schism" by "legitimizing the schismatic church in China.

[20] On May 11, 2022, Hong Kong police arrested Zen and four others who helped run the disbanded 612 Humanitarian Relief Fund for protesters, all on the charge of "collusion with foreign forces".

[citation needed] He was worried that these laws, if enacted without a thorough consultation process including a white paper, could easily lead to future violations of basic civil rights.

[27] In September 2023 he also attended the trial of pro-democracy media tycoon and founder of influential tabloid Apple Daily Jimmy Lai.

[28] On 5 June 2005, Zen announced that if the Legislative Council passed a proposal to support the schools to create incorporated management committees on 8 July 2005, he would appeal against the decision to the court.

He added that he believed that many people who had been hurt by the restrictions "have never given the smallest reason to be suspected of not accepting the liturgical reform of the [Second Vatican Council].

[32] About one month later, several unions in Hong Kong Police Force decided to write a letter to the Pope to complain about Zen's speech.