Pesky was born in Portland, Oregon, the son of Croat immigrants Jakov and Marija (Bajama) Paveskovich. (Major League Baseball has his date of birth as September 27, 1919, an adjustment made by Pesky in 1939 to meet baseball scouting age limits for tryouts.)  Pesky played for Lincoln High School, and spent several years playing for local amateur teams, such as the Portland Babes, Bend Elks and Silverton Red Sox. The third of these teams was associated with the Silver Falls Timber Company, which was owned by Tom Yawkey, who also owned the major league Red Sox. A skilled ice hockey player, he once worked out with the Boston Bruins. Early in his playing career, Portland sportswriters would abbreviate his name to “Pesky” because it fit better in a box score. He would legally change his name to Pesky in 1947.

Pesky was signed as an amateur free agent by the Red Sox before the 1940 season and spent the next two seasons in the minor leagues. In 1940, he played for the Rocky Mount Red Sox of the Piedmont League, where he was a teammate of future Hall of Famer Heinie Manush, who was the team’s player-manager. After hitting .325 with Rocky Mount, he moved up to the double-A Louisville Colonels, where he also batted .325. The next year, he was in the major leagues.

During his rookie year in 1942, Pesky led the AL in hits with 205—at the time a record for a rookie—as well as sacrifice hits with 22. He was second only to teammate Ted Williams in average at .331, and finished third in Most Valuable Player voting behind MVP Joe Gordon and Williams.  After missing three seasons due to World War II, Pesky came back in 1946 and seemed not to miss a beat, leading the league in hits once again, batting .335, third in the league, and finishing fourth in the MVP voting while also making his first and only All-Star team. His 53 hits in August set a team record for hits in a month, a record later tied by Dom DiMaggio. In 1947, Pesky batted .324 while leading the league in hits for the third consecutive year with 207.

In the 1947–48 offseason, the Red Sox traded six players and $310,000 in cash to the St. Louis Browns for Vern Stephens and Jack Kramer. Stephens, a three-time All-Star, was also a shortstop, and Pesky was asked to move to third base. The switch took a toll on Pesky, who had his worst season to date as a hitter, as his average dropped to .281. He bounced back to hit over .300 each year from 1949 to 1951, and in 1951 he and Stephens swapped positions, with Pesky returning to short and Stephens moving to third base.

Pesky began the 1952 season very slowly, and by mid-June he had played in just 25 games, batting .149. He was traded to the Detroit Tigers in a nine-player deal. He split time at shortstop with Neil Berry, batting .254 in 69 games with the Tigers. In 1953, the Tigers moved Pesky to second base, and his batting average rebounded somewhat to .292. However, in 1954, the Tigers installed rookie Frank Bolling at second base, and Pesky was demoted to the bench. He was traded in mid-season for the second time, this time to the Washington Senators, but after finishing the season batting just .246 overall, he was released.

Intermittently, Pesky was allowed to sit on the Red Sox bench during games, but three times was prevented from the task — once by his own general manager, Dan Duquette, a second time when the Baltimore Orioles complained to MLB, and a third time in March 2007, when Major League Baseball announced it would enforce limitations that only six coaches could be in uniform during a game. Pesky, as an instructor, was ineligible. On April 3, 2007, the North Shore Spirit, a now-defunct team in the Independent Can-Am League, in Lynn, Massachusetts invited Pesky to sit in their dugout — and serve as an honorary coach — anytime he wanted.

Pesky attended the 2004 World Series when the Red Sox met the Cardinals for a third time and watched the final out of Game 4, where the Red Sox sealed a sweep and their World Series win in 86 years, from the visiting clubhouse at Busch Stadium. In the celebration that immediately followed, he was embraced by members of the Curse-breaking, title-winning Sox such as Tim Wakefield, Curt Schilling and Kevin Millar as a living representative of past Red Sox stars whose teams had fallen short of winning the Fall Classic, at times literally at the final hurdle. As John Powers wrote for the Boston Globe, “Pesky was the stand-in for all of the Towne Teamers who’d gotten to the World Series and fell short. For teammate Ted Williams, who wept in the clubhouse after batting .200 in 1946. For Jim Lonborg, who won two games with brilliant pitching in 1967 but was battered on two days’ rest in the finale. For Carl Yastrzemski, who played on two teams that lost the Series in the seventh game. And for Bill Buckner, who had the grounder go between his legs in 1986.”

He played a poignant and prominent role in the ceremony in which the World Series Championship Rings were handed out (April 11, 2005 before the Red Sox home season opener against the Yankees) – and he himself was awarded the World Series ring that had eluded him as a player and manager. Bill Simmons, who was present that day, wrote for ESPN in a column that was republished in Now I Can Die In Peace that Pesky received the biggest cheer as a living “reminder of everything that had happened since 1918.” (As others had pointed out, not only had Pesky been the shortstop responsible during Slaughter’s Mad Dash, but he had been born in 1918 and his wife was named Ruth.) With the help of Carl Yastrzemski, he raised the 2004 World Series Championship banner up the Fenway Park center field flagpole. After the Red Sox swept the Colorado Rockies in the 2007 World Series, Pesky once again received a ring and was given the honor of raising the newest Red Sox Championship banner on April 8, 2008.

On his 87th birthday, September 27, 2006, the Red Sox honored Pesky by officially naming the right-field foul pole “Pesky’s Pole”, although it had already been unofficially known as such. On September 23, 2008, the Red Sox announced that they would retire the No. 6 Pesky wore as a player to mark his 89th birthday and his long years of service to the club. (Pesky wore No. 22 as the team’s manager in the 1960s, and No. 35 as a coach from 1975 to 1980. Although he reclaimed No. 6 and wore it from 1981 to 1984, between 1985 and its retirement the number also was assigned to players such as Bill Buckner, Rick Cerone, Damon Berryhill and Tony Peña.)

Pesky’s was the sixth number retired by the Red Sox; his number retired was the first to break the club’s code to have a number retired: being in the Baseball Hall of Fame and having spent at least ten years with the Red Sox (Pesky has not been selected for the Hall of Fame).  Pesky was a longtime resident of Boston’s North Shore, living in Lynn and then Swampscott, Massachusetts. He was a visible member of the community, making personal appearances for the Red Sox. For years, he was a commercial spokesman on television and radio for a local supplier of doors and windows, JB Sash and Door Company. The commercials were deliberately and humorously corny, with Pesky and the company’s owner calling themselves “the Window Boys.”

On May 16, 2009 Pesky was given an honorary degree during Salem State College’s 199th commencement ceremony. On April 20, 2012, Boston Red Sox fans celebrated the 100th birthday of Fenway Park, and Johnny Pesky was a participant. He was wheeled out to second base in a wheelchair, aside Bobby Doerr, to join over 200 past Red Sox players and coaches through the decades.  Pesky died on August 13, 2012, at the Kaplan Family Hospice House in Danvers, Massachusetts at the age of 93; he was buried next to his wife Ruth, who died in 2005. Many in Boston and in Red Sox Nation mourned his passing, and John Dennis began the first edition of the Dennis & Callahan Show on WEEI in Boston after his death by saying that it had felt like every New Englander’s grandfather had died when Pesky died.