Nicholas Thomas Brignola was born July 17, 1936, in Troy, New York, into a musical family; his father played tuba and an uncle played banjo. Largely self-taught, he started on clarinet at eleven and added alto and tenor saxophone and flute over the following years. At twenty, while studying education at Ithaca College, he dropped his alto off for repair and borrowed a baritone saxophone from the shop because it was the only horn available; he never went back to the smaller horns as his main voice. The Ithaca College group he played in won a 1957 DownBeat award for best college jazz group, which led to festival dates and an appearance at Café Bohemia in Greenwich Village. He went on to study at Berklee College of Music in Boston on a Benny Goodman Scholarship.

Through the late 1950s and into the 1960s Brignola worked the upstate New York circuit around Troy, Albany, and Schenectady with bandleaders Herb Pomeroy and Reese Markewich, then moved to the West Coast to play with vibraphonist Cal Tjader and the Mastersounds. He joined Woody Herman's orchestra in 1963 and spent 1963 to 1964 with guitarist Sal Salvador before returning to his home region in 1964, where he began leading his own groups, hosted a jazz radio program, and taught at local colleges. In 1967 he began an extended association with trumpeter Ted Curson, touring Europe with him in 1967 and appearing at the Newport and Monterey jazz festivals; the partnership continued on and off for years and brought Brignola his first sustained international exposure.

On December 22, 1977, at Blue Rock Studio in New York, Brignola led the session that became his best-known record: Baritone Madness, released in 1978 as the debut LP on the new Bee Hive label. Billed to "The Nick Brignola Sextet featuring Pepper Adams," it paired Brignola with Pepper Adams, one of his acknowledged idols on the instrument, alongside Ted Curson on trumpet and flugelhorn, pianist Derek Smith, bassist Dave Holland, and drummer Roy Haynes, running through bebop standards including "Donna Lee," "Billie's Bounce," and a reworking of "Ornithology" retitled "Marmeduke." He returned to the twin-baritone format the following year: Burn Brigade, recorded June 19, 1979, and issued in 1980 on Bee Hive, put him alongside fellow baritone players Ronnie Cuber and Cecil Payne, backed by pianist Walter Davis Jr., bassist Walter Booker, and drummer Jimmy Cobb. That same period produced two more leader dates for the Los Angeles-based Interplay and Seabreeze labels: New York Bound (recorded October 1978, released 1979), on which Brignola set the baritone aside to play alto, soprano, flute, and clarinet with pianist Walter Bishop Jr., bassist Sam Jones, and drummer Roy Haynes, and L.A. Bound (1980, Seabreeze), with trombonist Bill Watrous and drummer Dick Berk, which earned Brignola a 1980 Grammy nomination.

In the mid-1970s he had also joined the fusion group Petrus, led by pianist Phil Markowitz, and he kept a busy regional performing schedule for the rest of his career, including a long-running "Many Styles of Nick Brignola" concert series and regular sets at the Ramada Inn in Schenectady. His quartet album Signals...In from Somewhere (recorded June 1983 in Utica, New York, released on Discovery) featured pianist Bill Dobbins, bassist John Lockwood, and drummer David Calarco. From 1988 onward Brignola recorded a long, well-documented series of albums for Reservoir Records, beginning with Raincheck (recorded September 1988 at Van Gelder Studio with Kenny Barron, George Mraz, and Billy Hart) and continuing through On a Different Level (1989), What It Takes (1991), It's Time (1991), Live at Sweet Basil, First Set (recorded live August 28, 1992, released 1994), Like Old Times (1994), The Flight of the Eagle (recorded June 1996 with Kenny Barron, Rufus Reid, and Victor Lewis), Poinciana (recorded April 1997 at Van Gelder Studio with Phil Markowitz, Steve LaSpina, and Billy Hart), and All Business (1999, with guitarist Chuck D'Aloia, vibraphonist Dave Pike, bassist John Patitucci, and drummer Billy Hart).

Brignola continued performing and recording even as his health declined. His final studio album, Tour de Force, was recorded in 2001 with guitarist Chuck D'Aloia, bassist Eddie Gomez, and drummer Bill Stewart, and was released on Reservoir on February 26, 2002, eighteen days after he died. Nick Brignola died of cancer on February 8, 2002, at Albany Medical Center in Albany, New York, at age 65. A second volume from the 1992 Sweet Basil engagement, Things Ain't What They Used to Be: Last Set at Sweet Basil, appeared posthumously on Reservoir in 2003.

Brignola named Harry Carney, Duke Ellington's baritone anchor for four decades, as his primary influence, but his own playing owed as much to his unusual route to the horn: because he came up first on clarinet, alto, and tenor, he brought an agility and speed to the baritone that few players of his generation matched, letting him navigate bebop's fastest tempos and most angular lines on an instrument built for weight rather than quickness. Reviewers consistently paired him with Pepper Adams and Cecil Payne as the era's three leading hard-bop baritone specialists, and the two summit-meeting albums he built around exactly that comparison, Baritone Madness with Adams and Burn Brigade with Adams's contemporaries Cuber and Payne, remain his most cited work. AllMusic's Scott Yanow described Baritone Madness as living up to its title, with "quite a few sparks" flying between the two horns, and called the Burn Brigade three-way baritone match a fight fought "to a draw." His later Reservoir recordings drew notice for a different quality: AllMusic's Mark Romano wrote that Brignola combined "muscular phrasing with a supreme sensitivity," and JazzTimes praised a sound "silky smooth and possessed of honest emotion" on ballad material.