Lowe began his acting career in the 1980s when he appeared in a number of television films. Lowe co-starred with Charlie Sheen in the 1984 CBS Television drama Silence of the Heart. In 1988 he co-starred with Tommy Lee Jones and Robert Urich in the made-for-TV film April Morning, which depicted the battle of Lexington in the American Revolutionary War. Lowe played the title character in the short-lived sitcom, Spencer, which he left after six episodes.

From 1991 to 1993, he starred in Life Goes On, for which he received the Primetime Emmy Award for Outstanding Supporting Actor in a Drama Series in 1993.

While filming Quiet Days in Hollywood, Lowe met actress Hilary Swank. They married on September 28, 1997. On January 9, 2006, Lowe and Swank announced their separation, and in May 2006, they announced their intention to divorce. The divorce was finalized on November 1, 2007. Swank infamously forgot to thank Lowe during her acceptance speech after winning her first Academy Award in 2000 (for Boys Don’t Cry). Upon winning her second Oscar in 2005 for Million Dollar Baby, Lowe was the first person she thanked.

Lowe had recurring roles on Melrose Place, Popular, Now and Again, and ER, and guest-starring roles on Touched by an Angel, Superman, CSI: Miami and Medium. Lowe’s feature film appearances have included roles in Nobody’s Perfect, True Blood, Quiet Days in Hollywood, Floating, and Unfaithful. In 2000 he portrayed iconic singer John Denver in the made-for-television movie Take Me Home. That year he also wrote and directed the short film The Audition. Lowe made his feature film directorial debut in 2007 with Beautiful Ohio. Lowe has directed episodes of Bones, Brothers and Sisters, Law & Order: Special Victims Unit, Hack, Without a Trace, and Pretty Little Liars.

On January 19, 2007, a representative announced that Lowe was dating producer Kim Painter. Lowe and Painter’s daughter Mabel Painter Lowe was born on May 16, 2009. Lowe and Painter were married on August 28, 2010, in a small ceremony in Los Angeles. They welcomed their second daughter, Fiona Hepler Lowe, on November 15, 2012. Hepler was Lowe’s late mother’s maiden name. They welcomed their third daughter, Nixie Barbara Lowe, on March 18, 2016.

In April 2010, Lowe replaced Alexis Denisof as Aria’s father, Byron Montgomery, in Pretty Little Liars.