Born in Seville on 30 January 1846, at 5 Plaza de Santa Lucia, she was baptised on 2 February in the Church of Santa Lucia under the name María de los Angeles.
The family was humble. Her father, Francisco Guerrero, was a wool carder from Grazalema who had moved to Seville. Her mother, Josefa González, was from Seville, a daughter of parents born in Arahal and Zafra. She was one of 14 children, of whom only six reached adulthood.
Both of Guerrero’s parents worked in a priory of the Trinitarian friars in Seville, her father as a cook and her mother as a laundress and seamstress. Her schooling was limited, as was typical of young girls of that social class at that time. She received her first communion when she was eight years old and confirmation when she was nine. At 12 years of age she went to work in a shoe repair shop to help the family income, and remained there almost continuously until she was 29.
Guerrero’s supervisor at the shoe repair shop was Antonia Maldonado, a devout lady who encouraged her employees to pray together, recite the rosary and read about the lives of saints. Through her, when she was 16 years old, Guerrero was introduced to José Torres y Padilla, a priest from the Canary Islands with a reputation for holiness, who was Maldonado’s spiritual director. He became Guerrero's spiritual guide and confessor and came to have a major influence on her.
In 1865, at age 19, Guerrero applied to enter the monastery of the Discalced Carmelite nuns in Seville as a lay sister. Her application, however, was denied because the state of her health seemed inadequate for the heavy physical work demanded of those members of the monastic community. She was then advised by Torres to start work among the ill, particularly those suffering from cholera, which was rife at that time. Three years later, in 1868, she applied again to enter consecrated life, this time to the Daughters of Charity in Seville and, although still not well, she was accepted. The sisters attempted to nurse her to full health, sending her to Valencia to recover, but Guerrero finally had to leave the convent during her novitiate and returned to work in the shoe factory. During this time she kept a detailed spiritual diary which revealed the style and life ideals that she felt called to live.
On 2 August 1875 Guerrero (now 29 years old) left the shoe shop and was joined by three other women, Josefa de la Peña, who was wealthy, and Juana María Castro and Juana Magadán, both from poor families like hers who established themselves as a religious community. Torres assumed the position of director of the new institute and appointed Guerrero the sister superior of the community. With money from De la Peña, they had rented a small room with access to a kitchen at 13 San Luis Street in Seville and from there they organized a day and night support service for the local poor and ill. At that time, they began to wear a religious habit and Guerrero took the religious name of Mother Angela of the Cross.
The community received official approval on 5 April 1876 from Luis de la Lastra y Cuesta, the cardinal archbishop of Seville. In 1877 a second community was founded in Utrera, in the Province of Seville, and later another in Ayamonte. Torres died in the same year and his place as director of the institute was taken by his protegee, José María Alvarez y Delgado. That same year, Guerrero took her perpetual religious vows under him. Soon 23 communities of the new institute came to be founded, mostly around western Andalucia and southern Extremadura.
Guerrero died in Seville on 2 March 1932 from natural causes, aged 86, and was entombed in the Sisters of the Cross Convent. 71 years later, on 4 May 2003, her body was transferred to Seville Cathedral as part of the celebration of her canonization. Her body remained on display for a week in a glass-sided coffin until it was returned to the convent on 11 May.
As the first step in Guerrero's canonization, she was declared venerable on 12 February 1976 by Pope Paul VI. She was beatified on 5 November 1982 by Pope John Paul II in Seville. Finally she was declared a saint on 4 May 2003 by Pope John Paul II in the Plaza de Colón in Madrid.