Escalante was born in 1930 in La Paz, Bolivia. Both of his parents were teachers. Escalante was proud of his Aymara heritage.

In 1974, he began to teach at Garfield High School. Escalante eventually changed his mind about returning to work when he found 12 students willing to take an algebra class.

Escalante continued to teach at Garfield and instructed his first calculus class in 1978. He recruited fellow teacher Ben Jiménez and taught calculus to five students, two of whom passed the AP calculus test. The following year, the class size increased to nine students, seven of whom passed the AP calculus test. By 1981, the class had increased to 15 students, 14 of whom passed. Escalante placed a high priority on pressuring his students to pass their math classes, particularly calculus. He rejected the common practice of ranking students from first to last but frequently told his students to press themselves as hard as possible in their assignments.

In 1982, Escalante first gained media attention when 18 of his students passed the Advanced Placement Calculus exam. The Educational Testing Service found the scores to be suspicious because they all made exactly the same math error on the sixth problem, and they also used the same unusual variable names. Fourteen of those who passed were asked to take the exam again. Twelve of them agreed to retake the test, and all did well enough to have their scores reinstated.

In 1983, the number of students enrolling and passing the calculus test more than doubled. That year, 33 students took the exam, and 30 passed. That year, he also started to teach calculus at East Los Angeles College. By 1987, 73 students passed the AB version of the exam, and another 12 passed the BC version. That was the peak for the calculus program. The same year, Gradillas went on sabbatical to finish his doctorate with hopes that he could be reinstated as principal at Garfield or a similar school with a similar program upon his return.

In 1988, a book, Escalante: The Best Teacher in America by Jay Mathews, and a film, Stand and Deliver, were released based on the events of 1982. Teachers and other interested observers asked to sit in on his classes. He shared with them: “The key to my success with youngsters is a very simple and time-honored tradition: hard work for teacher and student alike.” Escalante received visits from political leaders and celebrities, including President Ronald Reagan and actor Arnold Schwarzenegger. In 1990, Escalante worked with the Foundation for Advancements in Science and Education to produce the video series Futures, which won a Peabody Award.

In his final years at Garfield, Escalante received threats and hate mail. By 1990, he had lost the math department chairmanship. Escalante’s math enrichment program had grown to more than 400 students. His class sizes had increased to over 50 students in some cases. That was far beyond the 35 student limit set by the teachers’ union, which increased its criticism of Escalante’s work. In 1991, the number of Garfield students taking advanced placement examinations in math and other subjects jumped to 570. The same year, citing faculty politics and petty jealousies, Escalante and Jiménez left Garfield. Escalante found new employment at Hiram W. Johnson High School in Sacramento, California. At the height of Escalante’s success, Garfield graduates were entering the University of Southern California in such great numbers that they outnumbered all the other high schools in the working-class East Los Angeles region combined. Even students who failed the AP exam often went on to study at California State University, Los Angeles.

Angelo Villavicencio took over the program after Escalante’s departure, teaching the remaining 107 AP students in two classes over the following year. Sixty-seven of Villavicencio’s students went on to take the AP exam and forty-seven passed. The math program’s decline at Garfield became apparent following the departure of Escalante and other teachers associated with its inception and development. In just a few years, the number of AP calculus students at Garfield who passed their exams dropped by more than 80%. In 1996, Villavicencio contacted Garfield’s new principal, Tony Garcia, and offered to come back to help revive the dying calculus program. His offer was rejected.

In the mid-1990s, Escalante became a strong supporter of English-only education efforts. In 1997, he joined Ron Unz’s English for the Children initiative, which eventually ended most bilingual education in California schools.

In 2001, after many years of preparing teenagers for the AP calculus exam, Escalante returned to his native Bolivia. He lived in his wife’s hometown, Cochabamba, and taught at Universidad Privada del Valle [es]. He returned to the United States frequently to visit his children.

In early 2010, Escalante faced financial difficulties from the cost of his cancer treatment. Cast members from Stand and Deliver, including Edward James Olmos, and some of Escalante’s former pupils, raised funds to help pay for his medical bills.

Escalante died on March 30, 2010 at his son’s home while undergoing treatment for bladder cancer. He was 79.

On April 1, 2010, a memorial service honoring Escalante was held at the Garfield High School. Students observed a moment of silence on the front steps of the campus. A wake was also held on April 17, 2010 in a classroom at Garfield.

Escalante is buried at Rose Hills Memorial Park in Whittier Lakeside Gardens. In 2016, the United States Postal Service issued a commemorative stamp in his likeness.