Milby opened in March 1926, replacing the former Harrisburg High School (1911-1926), which was located several blocks south of Milby. Thirteen teachers and 212 students formed Milby's initial population.

In December 1991 Milby was one of the largest high schools in Texas, with 3,617 students. In 2007 John Hopkins University referred to Milby as a 'passing factory' where at least 90% percent of the entering freshman class make it to their senior year. During that year 90% percent of high schoolers moved to Milby because of their education program. Over the course of the 2010–2011 school year, Milby had 2,156 students: 95% Hispanic, 3% African-American, 1% Asian and 1% White .

Milby's Petroleum-Chemical Academy opened in the fall of 2008. Milby also contains HISD's Science Institute Magnet Program. Newsweek named Milby "One of America's Best High Schools" in 2009. Milby High School was named one of the Best Urban Comprehensive High Schools as reported by the Houston Chronicle, Sunday, April 25, 2010. Milby's alumni include current and former community leaders, business owners, educators, local and state politicians, members of the media, professional athletes and entertainers.

Milby is a TEA Recognized campus with a unique five-point STEM Magnet House program offering unique career and college preparatory programs. Advanced Placement courses and Houston Community College Dual-Credit courses are available on site.