The prototype of the Lockheed Model 18, which first flew in 1939, was constructed from one of a batch of Lockheed Model 14 Super Electras which had been returned to the manufacturer by Northwest Airlines after a series of crashes of Model 14s. The fuselage was lengthened by 5 ft (1.5 m), enabling the fitting of two more rows of seats and hopefully making the aircraft more economical to operate. However, most US airlines were by then committed to purchasing the Douglas DC-3, and Lockheed found the Lodestar difficult to sell at home.  A total of 625 Lodestars of all variants were built.

Overseas sales were a little better, with 29 bought by the government of the Netherlands East Indies. South African Airways (21), New Zealand National Airways Corporation (13), Trans-Canada Air Lines (12) and BOAC (9) were the biggest airline customers. Various Pratt & Whitney and Wright Cyclone powerplants were installed.

When the United States started to build up its military air strength in 1940–41, many American operated Lodestars were impressed as the C-56. This was followed by the construction of many new-build Lodestars which were flown by the Army Air Force as the C-60 and U.S. Navy as the R5O. Lend-lease aircraft were used by the RNZAF as transports.

One bought in 1942 to serve as Brazilian President Getúlio Vargas' personal aircraft. This aircraft was specially designed for that purpose and had 11 seats.

After the war many Lodestars were overhauled and returned to civilian service, mostly as executive transports such as Dallas Aero Service's DAS Dalaero conversion, Bill Lear's Learstar (produced by PacAero), and Howard Aero's Howard 250.  A few of the latter were even converted to tricycle undercarriage.

Many of the New Zealand aircraft were later used for aerial topdressing.

A single Lodestar served with the Israeli Air Force during the 1948 Arab-Israeli War.

A number of skydiving operations in the United States used Lodestars during the 1970s and 1980s.