Piller was born in New York, USA. With parents who were both involved in writing, his father as a Hollywood screenwriter and his mother as a songwriter, he planned to be a scriptwriter from an early age. However a college lecturer discouraged him, and Piller started out in television working as an Emmy Award-winning journalist for CBS News in New York, WBTV in Charlotte, North Carolina, and WBBM-TV in Chicago, Illinois. However he then moved to Los Angeles, California and the entertainment side of television in the late 1970s, working as a censor and then a programming executive for CBS. He began writing scripts for television, and after selling a script to Cagney & Lacey and another to Simon & Simon, he was offered a staff writing position on Simon & Simon, where he stayed for three years, becoming a producer.

In 1989 a call to Maurice Hurley, a friend who had led the writing staff of The Next Generation through its second year, led to Piller co-writing an episode with Michael Wagner called "Evolution". After Wagner dropped out of leading the writing staff for the show's third year, Piller was invited to assume the lead position from the fifth episode of the third season, "The Bonding". During the first two years of the series, the writing staff had been plagued with conflicts, with the staff continually changing as different writers came and went; within a year, Piller had managed to form a strong writing team, something that had eluded previous executives. He also moved the direction of stories away from "alien of the week" or "situation of the week" to stories about the characters, which many point to as the turning point for the series. Piller also implemented an open door policy for scripts, that let anyone submit their story ideas and led to some of the most popular episodes, including "Yesterday's Enterprise". The Next Generation ran for seven years, receiving a number of awards including an Emmy Award nomination in its final year for Outstanding Drama Series. He received credit for a number of popular episodes, including "The Best of Both Worlds", Part 1 & 2, which are frequently identified as the best episodes of The Next Generation, and the two-part fifth season "Unification", which saw the appearance of Spock.

In late 1991, when The Next Generation executive producer Rick Berman was asked by Paramount Pictures to create a new Star Trek series, he turned to Piller to help him create the new show. Deep Space Nine debuted in January 1993 with a pilot script written by Piller, "Emissary", to the highest-ever ratings for a syndicated series premiere, and like The Next Generation ran for seven years. Again in 1994, Berman was asked to create another new Star Trek series for Paramount's new UPN television network and approached Piller to work with him in developing Voyager along with Jeri Taylor.

At the same time, Piller developed another series for UPN called Legend. However the series was cancelled after only 12 episodes. Meanwhile, Piller continued as a creative consultant on Deep Space Nine and Voyager, sending in notes on scripts as they were being prepared for production.

In 1993, Piller had been approached to write one of two prospective scripts for the first Next Generation feature film, with the other written by The Next Generation staff writers Ronald D. Moore and Brannon Braga. He declined. In 1997, he was approached again to write a Next Generation feature film, collaborating with Rick Berman to write Insurrection.

In 1996, he sold his first feature film script, called Oversight. The script, set in a Congressional sub-committee, is about "the passing of control from one generation to the next set", inspired by his relationship with his son Shawn, who had contributed scripts to The Next Generation and Voyager. the script has yet to be produced.

Piller formed a production company with his son Shawn in 1999 called Piller². Together they developed a pilot in 2000 for the WB Television Network called Day One. However the series was not picked up.

In 2001, he was approached by producer Lloyd Segan to develop a television series from Stephen King's novel The Dead Zone. The series The Dead Zone, co-developed with his son Shawn and starring Anthony Michael Hall, debuted June 16, 2002 on the USA Network. As of late 2007, USA Network canceled The Dead Zone series due to a lack of ratings.

In 2005, Wildfire debuted on the ABC Family channel, starring Deep Space Nine's Nana Visitor, another series that Piller developed with his son. Its fourth and final season ended on May 26, 2008.

On November 2, 2005, StarTrek.com announced that Piller had succumbed to head and neck cancer and died at his home.