From Cartagena, he passed to the newly created Diocese of Zipaquirá, when Pope Pius XII, through the papal bull of 1 May 1952, appointed him as its first bishop.

Because of his great devotion to the Virgin,[5] Botero asked the Holy Father to declare her the patron saint of the new diocese, under the title of the Assumption.

Pius XII, accepting his request, issued the papal bull of 2 August 1952, by which he appointed the Blessed Virgin of the Assumption as patron of the diocese.

He was one of the forty bishops who signed the Pact of the Catacombs of Domitilla, through which they committed to sharing time with the poor, assuming a simple lifestyle and renouncing all symbols of power.

[7][8] In Medellín, he reformed the archdiocesan curia; he built the current building of the Major Seminary in the Loreto sector; allowed the entry of various religious communities; held the third diocesan synod; had Miguel Antonio Medina Medina and Octavio Betancourt Arango as auxiliary bishops and Alfonso López Trujillo as coadjutor archbishop, who later succeeded him at the See.

He promoted the Faculty of Theology at the Universidad Pontificia Bolivariana and allowed seminarians to study at said university;[9] he founded the Bachilleres seminary, which lasted forty years.

He established Casa Pablo VI in 1971 and gave it statutes in 1977, for special vocations of students who had to work to financially support their families.