Schulz loved drawing and sometimes drew his family dog, Spike, who ate unusual things, such as pins and tacks. In 1937, Schulz drew a picture of Spike and sent it to Ripley's Believe It or Not!; his drawing appeared in Robert Ripley's syndicated panel, captioned, "A hunting dog that eats pins, tacks, and razor blades is owned by C. F. Schulz, St. Paul, Minn." and "Drawn by 'Sparky'" (C.F. was his Father, Carl Fred Schulz).

In February 1943, Schulz's mother Dena died after a long illness. At the time of her death, he had only recently been made aware that she suffered from cancer. Schulz had by all accounts been very close to his mother and her death had a big effect on him.

After being discharged in late 1945, Schulz returned to Minneapolis. He did lettering for a Roman Catholic comic magazine, Timeless Topix, and then, in July 1946, took a job at Art Instruction, Inc., reviewing and grading lessons submitted by students. Schulz had taken a correspondence course from the school before he was drafted. He worked at the school for several years while developing his career as a comic creator until he was making enough money to do that full-time.

Schulz's first group of regular cartoons, a weekly series of one-panel jokes called Li'l Folks, was published from June 1947 to January 1950 in the St. Paul Pioneer Press, with Schulz usually doing four one-panel drawings per issue. It was in Li'l Folks that Schulz first used the name Charlie Brown for a character, although he applied the name in four gags to three different boys as well as one buried in sand. The series also had a dog that looked much like Snoopy. In May 1948, Schulz sold his first one-panel drawing to The Saturday Evening Post; within the next two years, a total of 17 untitled drawings by Schulz were published in the Post, simultaneously with his work for the Pioneer Press. Around the same time, he tried to have Li'l Folks syndicated through the Newspaper Enterprise Association; Schulz would have been an independent contractor for the syndicate, unheard of in the 1940s, but the deal fell through. Li'l Folks was dropped from the Pioneer Press in January 1950.

Later that year, Schulz approached United Feature Syndicate with the one-panel series Li'l Folks, and the syndicate became interested. By that time Schulz had also developed a comic strip, usually using four panels rather than one, and to Schulz's delight, the syndicate preferred that version. Peanuts made its first appearance on October 2, 1950, in seven newspapers. The weekly Sunday page debuted on January 6, 1952. After a somewhat slow beginning, Peanuts eventually became one of the most popular comic strips of all time, as well as one of the most influential. Schulz also had a short-lived sports-oriented comic strip, It's Only a Game (1957–59), but he abandoned it after the success of Peanuts. From 1956 to 1965 he contributed a single-panel strip, "Young Pillars", featuring teenagers, to Youth, a publication associated with the Church of God.

In April 1951, Schulz married Joyce Halverson (no relation to Schulz's mother Dena Halverson Schulz). Later the same year, they moved to Colorado Springs, Colorado. Their first child, a son named Monte, was born in February 1952, and three more children were born later, in Minnesota.

The first collection of Peanuts strips was published in July 1952 by Rinehart & Company. Many more books followed, greatly contributing to the strip's increasing popularity. In 2004, Fantagraphics began their Complete Peanuts series. Peanuts also proved popular in other media; the first animated TV special, A Charlie Brown Christmas, aired in December 1965 and won an Emmy award. Numerous TV specials followed, the latest being Happiness is a Warm Blanket, Charlie Brown in 2011. Until his death, Schulz wrote or co-wrote the TV specials and carefully oversaw their production.

In 1957 and 1961 he illustrated two volumes of Art Linkletter's Kids Say the Darndest Things, and in 1964 a collection of letters, Dear President Johnson, by Bill Adler.

Schulz and his family returned to Minneapolis and stayed until 1958. They then moved to Sebastopol, California, where Schulz built his first studio. (Until then, he'd worked at home or in a small rented office room.) It was there that Schulz was interviewed for the unaired television documentary A Boy Named Charlie Brown. Some of the footage was eventually used in a later documentary, Charlie Brown and Charles Schulz. Schulz's Father died while visiting him in 1966, the same year Schulz's Sebastopol studio burned down. By 1969, Schulz had moved to Santa Rosa, California, where he lived and worked until his death. While briefly living in Colorado Springs, Schulz painted a mural on the bedroom wall of his adopted daughter Meredith Hodges, featuring Patty with a balloon, Charlie Brown jumping over a candlestick, and Snoopy playing on all fours. The wall was removed in 2001, donated and relocated to the Charles M. Schulz Museum in Santa Rosa.

Reared in a nominally Lutheran family, Schulz had been active in the Church of God (Anderson, Indiana) as a young adult and later taught Sunday school at a United Methodist Church. In the 1960s, Robert L. Short interpreted certain themes and conversations in Peanuts as consistent with parts of Christian theology, and used them as illustrations in his lectures on the Gospel, as explained in his book The Gospel According to Peanuts, the first of several he wrote on religion, Peanuts, and other popular culture.

A proponent of manned space FLIGHT, Schulz was honored with the naming of Apollo 10 command module Charlie Brown, and lunar module Snoopy launched on May 18, 1969. The Silver Snoopy award is a special honor awarded to NASA employees and contractors for outstanding achievements related to human FLIGHT safety or mission success. The award certificate states that it is "In Appreciation" "For professionalism, dedication and outstanding support that greatly enhanced space FLIGHT safety and mission success."

By Thanksgiving 1970, it was clear that Schulz's marriage was in trouble. He was having an affair with a 25-year-old woman named Tracey Claudius. The Schulzes divorced in 1972, and in September 1973 he married Jean Forsyth Clyde, whom he had first met when she brought her daughter to his hockey rink. They were married for 27 years, until Schulz's death in 2000.

On January 1, 1974, Schulz served as the Grand Marshal of the Rose Parade in Pasadena, California.

From the late 1980s, Schulz said in interviews that some people had described him as a "secular humanist" though he didn't know one way or another:

In July 1981, Schulz underwent heart bypass surgery. During his hospital stay, President Ronald Reagan phoned to wish him a quick recovery.

On July 1, 1983, Camp Snoopy opened at Knott's Berry Farm, a forested, mountain theme area featuring the Peanuts characters. It has rides designed for younger children and is one of the most popular areas of the amusement park.

On Sunday, May 8, 1988, two gunmen in ski masks entered the Schulzes' home through an unlocked door, planning to kidnap Jean, but the attempt failed when their daughter Jill drove up to the house, prompting the would-be kidnappers to flee. Jill called the police from a neighbor's house. Sonoma County Sheriff Dick Michaelsen said, "It was obviously an attempted kidnap-ransom. This was a targeted Criminal act. They knew exactly who the victims were." Neither Schulz nor his wife was hurt during the incident.

Multiple biographies have been written about Schulz, including Rheta Grimsley Johnson's Good Grief: The Story of Charles M. Schulz (1989), which Schulz authorized.

When the Mall of America in Bloomington, Minnesota opened in 1992, the amusement park in the center of the mall was themed around Schulz's Peanuts characters, until the mall lost the rights to use the brand in 2006.

The Charles M. Schulz Museum counts Milton Caniff (Terry and the Pirates) and Bill Mauldin as key influences on Schulz's work. In his own strip, Schulz regularly described Snoopy's annual Veterans Day visits with Mauldin, including mention of Mauldin's World War II cartoons. Schulz (and critics) also credited George Herriman (Krazy Kat), Roy Crane (Wash Tubbs), Elzie C. Segar (Thimble Theatre) and Percy Crosby (Skippy) as influences. In a 1994 address to fellow cartoonists, Schulz discussed several of them. But according to his biographer Rheta Grimsley Johnson:

Schulz received the National Cartoonists Society's Humor Comic Strip Award in 1962 for Peanuts, the Society's Elzie Segar Award in 1980, and was also the first two-time winner of their Reuben Award for 1955 and 1964, and their Milton Caniff Lifetime Achievement Award in 1999. He was also an avid hockey fan; in 1981, Schulz was awarded the Lester Patrick Trophy for outstanding contributions to the sport of hockey in the United States, and he was inducted into the United States Hockey Hall of Fame in 1993. On June 28, 1996, Schulz was honored with a star on the Hollywood Walk of Fame, adjacent to Walt Disney's. A replica of this star appears outside his former studio in Santa Rosa. Schulz is a recipient of the Silver Buffalo Award, the highest adult award given by the Boy Scouts of America, for his Service to American youth.

Schulz was a keen bridge player, and Peanuts occasionally included bridge references. In 1997, according to Alan Truscott, the American Contract Bridge League (ACBL), awarded both Snoopy and Woodstock the honorary rank of Life Master, and Schulz was delighted. According to the ACBL, only Snoopy was awarded the honor.

In 1998, Schulz hosted the first Over 75 Hockey Tournament. In 2000, the Ramsey County Board voted to rename the Highland Park Ice Arena the Charles M. Schulz-Highland Arena in his honor.

Schulz was asked if, in his final Peanuts strip, Charlie Brown would finally get to kick the football after so many decades (one of the many recurring themes in Peanuts was Charlie Brown's attempts to kick a football while Lucy was holding it, only to have Lucy pull it back at the last moment, causing him to fall on his back). His response, "Oh, no. Definitely not. I couldn't have Charlie Brown kick that football; that would be a terrible disservice to him after nearly half a century." But in a December 1999 interview, holding back tears, Schulz recounted the moment when he signed his final strip, saying, “All of a sudden I thought, 'You know, that poor, poor kid, he never even got to kick the football. What a dirty trick—he never had a chance to kick the football.'”

In 2000, the Sonoma County Board of Supervisors renamed the county airport as the Charles M. Schulz - Sonoma County Airport in the cartoonist's honor. The airport's logo features Snoopy in goggles and scarf, taking to the skies on top of his red doghouse.

The Charles M. Schulz Museum and Research Center in Santa Rosa opened on August 17, 2002, two blocks away from his former studio, celebrating his life's work and the art of cartooning. A bronze statue of Charlie Brown and Snoopy stands in Depot Park in downtown Santa Rosa.

Santa Rosa, California, celebrated the 60th anniversary of the strip in 2005 by continuing the Peanuts on Parade tradition beginning with It's Your Town Charlie Brown (2005), Summer of Woodstock (2006), Snoopy's Joe Cool Summer (2007), and Look Out For Lucy (2008).

In 2006, Forbes ranked Schulz as the third-highest earning deceased Celebrity, as he had earned $35 million in the previous year. In 2009, he was ranked sixth. According to Tod Benoit, in his book Where Are They Buried? How Did They Die?, Charles M. Schulz's income during his lifetime totaled more than $1.1 billion.

Calvin and Hobbes creator Bill Watterson wrote in 2007: "Peanuts pretty much defines the modern comic strip, so even now it's hard to see it with fresh eyes. The clean, minimalist drawings, the sarcastic humor, the unflinching emotional honesty, the inner thoughts of a household pet, the serious treatment of children, the wild fantasies, the merchandising on an enormous scale—in countless ways, Schulz blazed the wide trail that most every Cartoonist since has tried to follow."

Schulz was the inaugural recipient of The Harvey Kurtzman Hall of Fame Award, accepted by Karen Johnson, Director of the Charles M. Schulz Museum, at the 2014 Harvey Awards held at the Baltimore Comic Convention in Baltimore, Maryland.

According to a 2015 "spiritual biography," Schulz's faith was complex and personal. He often touched on religious themes in his work, including the classic television cartoon, A Charlie Brown Christmas (1965), which features the character Linus van Pelt quoting the King James Version of the Bible Luke 2:8–14 to explain "what Christmas is all about." In interviews Schulz said that Linus represented his spiritual side, and the spiritual biography points out a much wider array of religious references.

Among the property damage from the October 2017 wildfires in California was the Santa Rosa home of Schulz.

Peanuts on Parade has been St. Paul, Minnesota’s tribute to its favorite native Cartoonist. It began in 2000 with the placing of 101 5-foot-tall (1.5 m) statues of Snoopy throughout the city of St. Paul. Every summer for the following four years, statues of a different Peanuts character were placed on the sidewalks of St. Paul. In 2001, there was Charlie Brown Around Town, 2002 brought Looking for Lucy, in 2003 along came Linus Blankets St. Paul, ending in 2004 with Snoopy lying on his doghouse. The statues were auctioned off at the end of each summer, so some remain around the city, but others have been relocated. The auction proceeds were used for artist's scholarships and for permanent, bronze statues of the Peanuts characters. These bronze statues are in Landmark Plaza and Rice Park in downtown St. Paul.