With Archbishop Charles J. Scicluna, Grech co-authored the Maltese bishops' pastoral guidelines on Amoris Laetitia, released in January 2017, which stated that in certain cases a divorced Catholic who remarried might receive communion after "honest discernment". The guidelines were republished in L'Osservatore Romano. The guidelines infamously said that:"the doctrine of the faith is capable of progressively acquiring a greater depth"and that addressing people in complex familial relations, or homosexuals or parents of homosexuals, "It is necessary to learn to speak that language which is known to contemporary human beings and who acknowledge it as a way of conveying the truth and the charity of the Gospel."
"If, as a result of the process of discernment, a separated or divorced person who is living in a new relationship manages, with an informed and enlightened conscience, to acknowledge and believe that he or she is at peace with God, he or she cannot be precluded from participating in the sacraments of Reconciliation and the Eucharist."In a December 2018 interview, he said he enjoyed discussions with atheists that sharpened his own beliefs and preferred dialogue to the confrontation his critics preferred. When asked about family and sexual issues he said:
If someone comes to me, asking me for help to discover Jesus Christ... he or she could be homosexual, and even in a homosexual relationship. It doesn’t matter. I will not impede that person; on the contrary I would help. The last thing I would do is take up a position against that person.... Before, we would say: 'put your life in order first, and then we’ll begin the journey towards God'. Today, on the other hand, we would say: 'Let us approach Jesus Christ... and Christ will help us put our lives in order.' ... 'Black' and 'white' still exist; but the grey area in-between has grown. It is in the grey areas that we must search. That’s why I said that I am wary of those priests, or Christians, who feel they already know all the answers. No one can make that claim. We all have to continue searching.On 2 October 2019, Pope Francis named him Pro-Secretary General of the Synod of Bishops, in anticipation of succeeding Cardinal Lorenzo Baldisseri when he retired as Secretary General. Grech worked alongside Baldisseri and participated as a member in the Synod of Bishops for the Pan-Amazon region. Grech was also the Apostolic Administrator of the Diocese of Gozo until 2020. He was one of five Synod officials who served ex offico on the fifteen-person commission that was responsible for drafting the final document of the Amazon Synod. In his first interview after his appointment he stated that
"there is a movement toward which the Church can acquire a greater feminine face that would also reflect Mary’s face". On 4 July 2020, Pope Francis named Grech a member of the Pontifical Council for Promoting Christian Unity, with the exception of reconciliation with traditional Catholic communities. On 25 October 2020, Pope Francis announced he would raise him to the rank of cardinal at a consistory scheduled for 28 November 2020. The previous Maltese cardinals were: Fabrizio Sceberras Testaferrata and Prospero Grech OSA .