Transportation Secretary Drew Lewis, generally regarded here as the most able domestic Cabinet officer in the administration, announced yesterday that he is resigning to take a job in private business, effective Feb. 1.

Lewis, 51, becomes the third Reagan Cabinet officer to move on. The others are former secretary of state Alexander M. Haig Jr. and former energy secretary James B. Edwards.

Both Lewis and White House spokesman Larry Speakes said yesterday that Lewis' departure was an isolated event, and not the start of a flurry of Cabinet-level shifts at this midpoint in the Reagan term. In fact, there was some speculation in the opposite direction: that lack of another attractive government job may have contributed to Lewis' decision to leave.

Lewis will become chairman and chief executive officer of Warner Amex Cable Communications Inc., a partnership of Warner Communications and American Express. Warner Amex is the nation's sixth largest cable TV company, and Lewis is taking over at a critical time for its cable venture. Story on Page F1.

Lewis' salary as a Cabinet secretary has been $69,630 a year. His new salary was not disclosed.

"I think the president has a fine Cabinet," Lewis said at yesterday's news conference. "My impression is most will be staying."

He said it was "totally unfair" to him and the administration to suggest that he had been under-utilized at the Transportation Department. He also said he had not been offered any other job in the administration, although he confirmed that he at one point had discussed taking on the chairmanship of the Republican National Committee, which ultimately went to Sen. Paul Laxalt (R-Nev.).

Lewis said at his news conference yesterday that he had offered to help Reagan as a volunteer if the president seeks reelection in 1984, but said later that because of his commitments to Warner Amex he would not be able to hold a full-time job in a second Reagan campaign.

Lewis' resignation had been rumored for some time and came as no surprise, either in the Transportation Department or at the White House. The Washington Post reported Dec. 16 that he was considering the Warner Amex job.

Lewis' letter of resignation was dated Dec. 12, a week and a half before the lame-duck session of Congress handed him the most impressive in a long list of accomplishments as secretary: a nickel-a-gallon increase in gasoline and other taxes for reconstruction of highways, bridges and mass transit systems.

Lewis, explaining the timing of his public announcement, said he had "a fundamental responsibility to the president" to see the highway tax-and-repair bill through the lame-duck session after he had fought hard for it within the administration.

Highway and transit interests were worried in the final days of the session that a Senate filibuster against the tax increase would succeed and they would be left with a far less able advocate than Lewis to carry on the fight next year.

Lewis shepherded the complex legislation through the House and the Senate, answering questions, cutting deals and generally keeping the bill on track.

Speakes said President Reagan considered Lewis "top notch" and "one of the most loyal and effective members of the Cabinet," and called passage of the gasoline tax increase his "major achievement."

Speakes said, "The president hopes to name a successor before Feb. 1, although the search is just now beginning." Lewis said the same thing, and said he had not been asked to recommend a successor, although he had some ideas if he were asked.

The two names most prominently mentioned in the transportation community in early speculation were those of Federal Highway Administrator Ray A. Barnhart, who was at Lewis' side throughout the gasoline tax fight, and Darrell M. Trent, currently deputy transportation secretary.

Others mentioned include Norbert Tiemann, federal highway administrator in the Ford administration; Edwin L. Harper, formerly deputy director of the Office of Management and Budget and now assistant to the president for policy and development, and John A. Clements, commissioner of New Hampshire's Department of Public Works and Highways, who has strong Republican credentials.

Edward J. King, defeated Democratic but conservative governor of Massachusetts, has been reported by the Boston press as actively seeking the job. Rep. Don H. Clausen (R-Calif.), who lost his bid for reelection, is intimately familiar with the Transportation Department as the outgoing ranking minority member of the House Public Works and Transportation Committee.

Lewis will be returning to the professional business career he has pursued for all but the past three years, when he was deputy political director of the Reagan-Bush Campaign Committee and then transportation secretary. His specialty has been saving failing firms.

His intimate knowledge of railroad operations came from nine years as trustee of the bankrupt Reading Railroad, which was ultimately conveyed to ConRail. ConRail, made up of several bankrupt northeastern railroads, is at a point where "it can be returned to the private sector," Lewis said in a letter to Reagan.

Lewis said the most difficult situation he faced as secretary concerned the strike in August, 1981, by the Professional Air Traffic Controllers Organization (PATCO), who worked for the Transportation Department's Federal Aviation Administration.

Lewis had tried to negotiate a new contract with PATCO personally, but when the 11,400 PATCO controllers struck, Reagan decided to fire them and Lewis supported his decision vigorously. The FAA set out to rebuild the air traffic system with supervisors, trainees and military controllers, and now claims that it is handling more than 90 percent of the traffic it did at the time of the strike.

Lewis also commissioned a major study of air traffic control procedures and supervisors' attitudes, and the study confirmed what controllers had been saying for years: that the FAA has significant management problems.

"I leave here with two regrets," Lewis said. "One is that we had to have the controllers' strike and it affected so many families, and the second is that I think it's very important that we rebuild the FAA so that some secretary of transportation in the future does not have the same problems that I had.

" . . . We had very serious personnel problems and they're not resolved yet, and they won't be because you don't change what's existed for 25 years in six months or a year. I would say in the FAA we have a two- to three- to four-year rebuilding program in terms of personnel policies and management. . . . I regret I will not be here to see that happen, but even if I stayed four years it would not have happened."

While the PATCO situation was not resolved happily, Lewis did for the aviation community the same thing he did later for highways and bridges: he nailed down a guaranteed source of funding to pay for the research and development of a new nationwide air traffic control computer system estimated to cost about $10 billion over the next decade.

New "user fees," the term Lewis always used in selling earmarked tax increases to the White House, will pay for the system as well as some of the operating and maintenance costs for existing air traffic control equipment, just as the the new gasoline tax will pay for the federal aid highway program.

Thus, two major components of the transportation budget will not have to compete with other domestic programs for money from the general fund.