The decision of Sen. Charles McC. Mathias Jr. (R-Md.) not to run for reelection next year delivers the sharpest blow yet to Republican hopes for keeping control of the Senate, strategists for both parties said yester-day.

Republicans enjoy a 53-47 majority in the chamber, but must defend 22 of the 34 seats to be contested next year.

Record budget deficits, trade imbalances and farm foreclosures, along with the historic inclination of voters to turn against the party of the White House six years into its administration, make the GOP's 1986 prospects shaky.

On top of that, three Republican incumbents have announced their retirement in the past six weeks -- Mathias, Sen. John P. East (N.C.) and Sen. Paul Laxalt (Nev.).

Of the three, Mathias' was the unkindest cut -- not because he is the party's most beloved member (his liberalism places him outside the Republican mainstream on many issues), but because he is among its most irreplaceable. Few other Republicans can hope to be elected statewide in as Democratic a state as Maryland.

"Even after the other two retirements, we still considered those two states leaning Republican," said David Narsavage, spokesman for the National Republican Senatorial Committee. "But in this case, we have to concede that the Democrats now start out with an edge."

Maryland has been one of the most Democratic states in the nation in the 1980s. In 1980, it was one of six states that President Jimmy Carter carried; in 1984, it ranked behind only Minnesota and Massachusetts in the percentage of its vote (47) for former vice president Walter F. Mondale.

Sen. George J. Mitchell (D-Maine), chairman of the Democratic Senatorial Campaign Committee, said the Mathias announcement "makes it increasingly clear we are going to take control. Some of these races are now starting to clarify, and I think it has been very advantageous for us."

Norman J. Ornstein, a congressional expert at the American Enterprise Institute, said the timing of the announcements, as candidate recruitment is under way in several key states, is especially fortuitous for the Democrats. "If you are making an assessment if your party is going to be in the majority . . . it makes it tougher for the Republicans to get the best candidates and to maintain their money margin."

With Mathias' announcement, there will be at least six vacant-seat Senate races next year. In addition to East and Laxalt, Republican Barry M. Goldwater (Ariz.) and Democrats Thomas F. Eagleton (Mo.) and Russell B. Long (La.) are stepping down.

More vacancies may yet develop. Sen. Gary Hart (D-Colo.) will announce early next year whether he will seek reelection or step down to concentrate on the presidency in 1988. If he does not run, Rep. Timothy E. Wirth (D-Colo.) is poised to seek the nomination, and some Colorado Democrats think he will be as strong a candidate.

In addition, Sen. Warren B. Rudman (R-N.H.) has done scant fund-raising this year and has mused publicly about taking a job in the private sector. In any event, that state is considered strongly Republican.