The most expensive high school built in Houston at the time, the campus was designed by the firm MacKie & Kamrath in a Frank Lloyd Wright-influenced modernist style.

The campus, described by the Houston Chronicle as "the finest Negro high school in the South," had a 1,500-seat auditorium, a gymnasium, an industrial arts facility, and a swimming pool.

[6] In May 1965, William Lawson, a youth minister, asked some Wheatley students to discuss a proposed school boycott.

John Nova Lomax of the Houston Press stated that pride and discipline at Wheatley began to disintegrate in the 1970s, as counselors complained about a low level of morale among the students.

In addition, many of Wheatley's new White teachers, many of whom did not live in the Fifth Ward, had a lack of experience in teaching inner city Black students.

In 1978 HISD proposed using smaller classes, higher teaching salary, and a redesigned educational program to ameliorate Wheatley's academic problems.

[2] In the mid-1980s, as crack cocaine became an epidemic in many inner-city neighborhoods, Wheatley students and teachers complained about security issues regarding some area apartments.

In 1985 three youngsters walked onto the campus and shot an English teacher who had been conducting drill team rehearsals in the cafeteria.

After Joan Raymond became superintendent in 1986, she considered closing Wheatley because of difficulties in making the school have acceptable academic achievement and safety.

In 1995 Wheatley had the highest dropout rate and lowest mathematics score of the high schools in Houston ISD.

[8] In 2007 a Johns Hopkins University study cited Wheatley as a "dropout factory" where at least 40% of the entering freshman class does not make it to their senior year.

[16] HISD plans to build the permanent Mickey Leland College Preparatory Academy for Young Men on the site of the former Carter Career Center.

Around that period the TEA was attempting to replace the HISD school board, and it could possibly use Wheatley's failing grade as evidence that it should take this action.

[19] In November of that year, TEA Commissioner Mike Morath announced that the appeal for Wheatley was rejected; the basis of the appeal submitted was that student scores should be waived due to Hurricane Harvey, but other schools did not get the waiver for that reason for that year.

Dan Hinde, a Texas state district judge, dismissed the lawsuits in December of that year.

[33] In 1997 Michael Berryhill of the Houston Press wrote that in the pre-desegregation era Wheatley "dominated black high school basketball in Texas" but it was not a "consistent power" in American football.

[6] The school won many trophies from the state basketball tournament, which was held at Prairie View A&M University.

[35] Historically the American football game between Wheatley and Yates High School was among the most prominent ones in the United States.

[37] The rivalry declined after Yates joined the UIL, and after the football leagues integrated the Thanksgiving Day Yates-Wheatley game ended.

Various famed musicians graduated from Wheatley in that time period,[5] including Arnett Cobb and Illinois Jacquet.