As the 1930s came, so did adversity. The Great Depression hit, and banks across the nation began to fail. Long lines formed, and when some banks weren`t able to produce the money people had in checking and savings accounts, they closed their doors, leaving people in financial disarray. The Bank of Alachua closed in 1931. However, some banks withstood the money runs, such as the First National Bank of Alachua. People coming out of the bank were asked how much money remained, and their assurances that there was plenty left helped return the confidence of those who had withdrawn their funds, and they returned to redeposit their money.

Watermelons were being grown in increasing number, and fresh corn, cucumbers, beans, and squash were being shipped to northern markets. Demonstrators from North Carolina showed people how to grow tobacco. Tobacco barns and packing sheds then began to replace cotton gins. In 1928, Copeland Sausage Company opened its doors.  This company would be the main employer in Alachua for nearly 50 years. It was first built near present day Hal Brady Recreation Center. However, it was illegal to kill the hogs inside the city limits. Therefore, the company would kill the hogs across the street (which was not in the city limits at the time). When the new plant was built, it was outside the city limits at the site of present day Copeland Park at Progress District.

Duke's Lumber Mill was a major employer at this time, and Alachua's Main Street became part of the Dixie Highway, a major roadway connecting much of the state. Enneis Motor Company installed two gasoline pumps and offered auto repair and service for travelers along the highway. The Lion's Club was established in 1931 to carry out civic improvement projects. The Alachua Woman's Club building was completed in 1938 as a project of the WPA, one of President Roosevelt's New Deal initiatives to provide work for the millions unemployed because of the Depression.

After World War II came, things were never the same in Alachua. Boys and girls left for the armed services, many never to return again. Families moved to find work in the shipyards or other war-related jobs. Most of the old buildings in town survived, though the old oaks that lined the street were cut down because of old age or to make room for new construction.