He began his career with Southwestern Bell in 1963 as a facility Engineer.

In October 1988, Whitacre became President and chief operating officer of a regional bell operating company, Southwestern Bell Corporation. Two years later, Whitacre became chairman of the board and chief executive officer. In 1995, Southwestern Bell Corporation changed its name to SBC Communications. Whitacre led SBC through a series of mergers and acquisitions in building the largest provider of both local long distance telephone services and wireless Service (through its Cingular division) in the United States. These acquisitions included Pacific Telesis (1997), SNET (1998), Comcast Cellular (1999), Ameritech (1999) and AT&T Corporation (2005), from which the post-merger company took its name, as well as the 2006 acquisition of Bell South.

BusinessWeek (1999) reported that, although the CEO of AT&T — amongst the largest and most influential names in telecommunications and its surrounding Technology, Whitacre did not use e-mail or have a computer at his office.

In 2004, he was awarded an honorary doctorate degree by the University of the Incarnate Word.

In 2006, Whitacre famously declared that companies like Google, Yahoo! or Vonage should not be able to “use the pipes for free.”

On April 27, 2007, at the AT&T annual stockholders meeting, Whitacre announced his intent to retire as chief executive officer and chairman of the board, effective June 3. The board of Directors elected Randall Stephenson to succeed Whitacre as new CEO and chairman. Whitacre retired on June 4, 2007, with Randall Stephenson taking over the following morning. Upon retirement, Whitacre was eligible for a $158 million payout from AT&T. Following retirement, under his employment contract, Whitacre was entitled to receive some continuing benefits, including automobile use, access to AT&T's corporate aircraft for up to ten hours per month, use of AT&T office facilities and support staff, home security, and club memberships, as well as payment of applicable taxes resulting from these benefits, except for use of the aircraft. In addition, Whitacre has a three-year consulting contract with AT&T for which he is paid about $1 million annually. It has been reported that during his tenure at AT&T, Whitacre offered Randall Stephenson three words of advice via text message when the executive change was announced: "Give 'em hell".

On November 12, 2008, Texas Tech announced that its college of engineering will be renamed the Edward E. Whitacre Jr. College of Engineering. In 2007, AT&T created an award called the "Whitacre Award" to honor the former chairman.

Whitacre was inducted into the Junior Achievement U.S. Business Hall of Fame in 2009.

In 2010, Whitacre was named as a finalist for Texan of the Year.

On Thursday, November 10, 2011, Whitacre was honored with the Amistad Award by the San Antonio-Mexico Friendship Council Inc (SAMFCO). This award recognized Whitacre as an individual who, according to SAMFCO, personifies the mission of said Council and for distinguishing himself by his dedication to strengthening and promoting the cultural and historical ties shared by the citizens of San Antonio and Mexico. The award ceremony was preceded by Tom C. Frost, senior chairman of the board of Frost National Bank, Henry E. Sauvignet, Director of Administration at the North American Development Bank (NADBANK), and Armando Ortiz Rocha, Consul General of Mexico in San Antonio. Whitacre is the 15th person to receive this award, sharing this grant with outstanding people such as Henry G. Cisneros, Juan Ramón de la Fuente, and the very own Tom C. Frost (Whitacre was the person who presided over the ceremony when Frost was given the award in 1999).

In February 2014 it was announced that he will deliver the Spring Commencement address for University of the Pacific's Stockton campus on May 10, 2014 at Alex G. Spanos Center.