During the 1950s and 1960s, Falwell spoke and campaigned against the U.S. civil rights Activist Martin Luther King Jr. and the racial desegregation of public school systems by the U.S. federal government. Liberty Christian Academy (LCA, founded as Lynchburg Christian Academy) is a Christian school in Lynchburg which was described in 1966 by the Lynchburg News as "a private school for white students."

In 1956, at age 22, Falwell founded the Thomas Road Baptist Church, originally located at 701 Thomas Road in Lynchburg, Virginia, with 35 members. The church went on to become a megachurch. Also in 1956, he began the Old Time Gospel Hour, a nationally syndicated radio and television ministry. When Falwell died, his son Jonathan became heir to his father's ministry, and took over as the senior pastor of the church. At this time, the weekly program's name was changed to Thomas Road Live.

In speaking of the Brown vs. Board of Education ruling, he said, in 1958:

On his evangelist program The Old-Time Gospel Hour in the mid 1960s, Falwell regularly featured segregationist politicians like Lester Maddox and George Wallace. About Martin Luther King he said: "I do question the sincerity and nonviolent intentions of some civil rights Leaders such as Dr. Martin Luther King Jr., Mr. James Farmer, and others, who are known to have left wing associations."

The Lynchburg Christian Academy later opened in 1967 by Falwell as a segregation academy and as a ministry of Thomas Road Baptist Church.

From the 1970s on, Falwell was involved in legal matters which occupied much of his time and propelled his name recognition.

In 1971, Jerry Falwell founded Liberty University. Liberty University offers over 350 accredited programs of study, with approximately 13,000 residential students and 90,000 online.

In 1972, the U.S. Securities and Exchange Commission (SEC) launched an investigation of bonds issued by Falwell's organizations. The SEC charged Falwell's church with "fraud and deceit" in the issuance of $6.5 million in unsecured church bonds. The church won a 1973 federal court case prosecuted at the behest of the SEC, in which the Court exonerated the church and ruled that while technical violations of law did occur, there was no proof the Church intended any wrongdoing.

By 1974, the Internal Revenue Service moved to revoke the tax-exempt status of Bob Jones University, which forbade interracial dating (blacks had been denied entry until 1971). The decisions infuriated Falwell. "In some states it's easier to open a massage parlor than to open a Christian school", Falwell complained.

Falwell condemned homosexuality as forbidden by the Bible. Gay rights groups called Falwell an "agent of intolerance" and "the founder of the anti-gay industry" for statements he had made and for campaigning against LGBT social movements. Falwell supported Anita Bryant's 1977 "Save Our Children" campaign to overturn a Florida ordinance prohibiting discrimination on the basis of sexual orientation and a similar movement in California. In urging the repeal of the ordinance, Falwell told one crowd, "Gay folks would just as soon kill you as look at you." When the LGBT-friendly Metropolitan Community Church was almost accepted into the World Council of Churches, Falwell called them "brute beasts" and stated, "this vile and satanic system will one day be utterly annihilated and there'll be a celebration in heaven." He later denied this. Falwell also regularly linked the AIDS pandemic to LGBT issues and stated, "AIDS is not just God's punishment for homosexuals, it is God's punishment for the society that tolerates homosexuals." Amongst many remarks over the years he is probably most known for statements attributed to him about a Teletubby being a homosexual role model for homosexual recruitment and stating that LGBT organizations angered God, thereby in part causing God to let the September 11 attacks happen.

What brought Falwell and other white evangelicals into Common cause with political conservatives was a ruling issued in 1978 by the IRS. This ruling stripped tax-exempt status from all-white private schools formed in the South in reaction to the Brown v. Board of Education mandate to desegregate public schools. Falwell had founded one of these schools in Lynchburg, though he and other white evangelicals insisted that their schools were Christian academies, not segregation academies. "In one fell swoop," writes political scientist Corey Robin, "the heirs of slaveholders became the descendants of persecuted Baptists, and Jim Crow a heresy the First Amendment was meant to protect." In this controversy, the Religious Right found its voice and its power. It also found Common cause with political conservatives.

The Heritage Foundation co-founder Paul Weyrich stated that Falwell launched the Moral Majority political action committee during 1979 to aid the Catholic public protest against legal abortion in the United States in response to U.S. President Jimmy Carter's "intervention against Christian schools" [the IRS intervention began during the Ford Administration] by "...trying to deny them tax-exempt status on the basis of so-called de facto segregation".

Falwell was an enemy of the revenge humorist "George Hayduke", who called Falwell a "fund-grubbing electronic Bible-banger" and "pious pride-in-the-pulpit". In his book Screw Unto Others, Hayduke mentions the story of Edward Johnson, who, in the mid-1980s, programmed his Atari home computer to make thousands of repeat phone calls to Falwell's 1–800 phone number, since Johnson claimed Falwell had swindled large amounts of money from his followers, especially Johnson's own mother. Southern Bell forced Johnson to stop after he had run up Falwell's telephone bill an estimated $500,000. At one point, prank callers, especially gay Activists, constituted an estimated 25% of Falwell's total calls, until the ministry disconnected the toll-free number in 1986.

In 1983, Larry Flynt's pornographic magazine Hustler carried a parody of a Campari ad, featuring a mock "interview" with Falwell in which he admits that his "first time" was Incest with his mother in an outhouse while drunk. Falwell sued for $45 million, alleging invasion of privacy, libel, and intentional infliction of emotional distress. A jury rejected the invasion of privacy and libel claims, holding that the parody could not have reasonably been taken to describe true events, but ruled in favor of Falwell on the emotional distress claim and awarded damages of $200,000. This was upheld on appeal. Flynt then appealed to the U.S. Supreme Court, which unanimously held that the First Amendment prevents public figures from recovering damages for emotional distress caused by parodies.

In 1984, Falwell was ordered to pay gay rights Activist and former Baptist Bible College classmate Jerry Sloan $5,000 after losing a court battle. In July 1984 during a TV debate in Sacramento, California, Falwell denied calling the homosexual-friendly Metropolitan Community Churches "brute beasts" and "a vile and Satanic system" that will "one day be utterly annihilated and there will be a celebration in heaven".

Funding for the film was provided by "Citizens for Honest Government", to which Falwell paid $200,000 in 1994 and 1995. In 1995 Citizens for Honest Government interviewed Arkansas state troopers Roger Perry and Larry Patterson regarding the murder conspiracy about Vincent Foster. Perry and Patterson also gave information regarding the allegations in the Paula Jones affair.

In 1999, Falwell declared the Antichrist would probably arrive within a decade and "of course he'll be Jewish". After accusations of anti-Semitism Falwell apologized and explained that he was simply expressing the theological tenet that the Antichrist and Christ share many attributes.

After the September 11 attacks in 2001, Falwell said on Pat Robertson's The 700 Club, "I really believe that the pagans, and the abortionists, and the feminists, and the gays and the lesbians who are actively trying to make that an alternative lifestyle, the ACLU, People For the American Way, all of them who have tried to secularize America. I point the finger in their face and say 'you helped this happen.'" Falwell further stated that the attacks were "probably deserved", a statement which Christopher Hitchens described as treason. After heavy criticism, Falwell said that no one but the terrorists were to blame, and stated, "If I left that impression with gays or lesbians or anyone else, I apologize."

In early 2005, Falwell was hospitalized for two weeks with a viral infection, discharged, and then rehospitalized on May 30, 2005, in respiratory arrest. President George W. Bush contacted Falwell to "wish him well". He was subsequently released from the hospital and returned to his duties. Later in 2005, a stent was implanted to treat a 70 percent blockage in his coronary arteries.

On July 31, 2006, Cable News Network's (CNN) Paula Zahn Now program featured a segment on "whether the crisis in the Middle East is actually a prelude to the end of the world". In an interview Falwell claimed, "I believe in the premillennial, pre-tribulational coming of Christ for all of his church, and to summarize that, your first poll, do you believe Jesus' coming the second time will be in the Future, I would vote yes with the 59 percent and with Billy Graham and most evangelicals."

The last televised interview with Jerry Falwell was conducted by Christiane Amanpour for the CNN original series CNN Presents: God's Warriors. He had been interviewed on May 8, one week before his death. Falwell's last televised sermon was his May 13, 2007, message on Mother's Day.

Falwell supported President George W. Bush's Faith Based Initiative, but had strong reservations concerning where the funding would go and the restrictions placed on churches. "My Problem is where it might go under his successors.... I would not want to put any of the Jerry Falwell Ministries in a position where we might be subservient to a Future Bill Clinton, God forbid.... It also concerns me that once the pork barrel is filled, suddenly the Church of Scientology, the Jehovah Witnesses [sic], the various and many denominations and religious groups—and I don't say those words in a pejorative way—begin applying for money—and I don't see how any can be turned down because of their radical and unpopular views. I don't know where that would take us."