In the 1930s, 1940s, and 1950s, 8th Street was often called "Beale Street West", reflecting a music and nightlife scene to equal that in Memphis. Some places in West Memphis have been associated with entertainers such as B.B. King (who began his public entertaining at the Square Deal Café on South 16th Street) and Elvis Presley (who ate his first breakfast after being inducted into the U.S.

Army at the Coffee Cup on East Broadway on March 24, 1958). Other night spots along Broadway Street included Willowdale Inn, the Cotton Club, and the Plantation Inn. Legal greyhound racing began in the county in 1935. In the years that followed, the track closed several times—once for flooding, another due to World War II, and another time due to fire.

However, the business currently known as Southland Park Gaming & Racing on North Ingram Boulevard has been in the same location since 1956 and is now open every day of the week, including 24 hours on weekends. West Memphis began its role as a trucking hub with the opening of parts of Interstate 55 in the 1950s.

With both I-55 and I-40 traveling toward the Mississippi River, West Memphis became known as the "crossroads of America" in the trucking industry. In 1973, a six-lane highway bridge, known as the Hernando de Soto Bridge and located north of the Harahan, opened as part of I-40. In 1980, Leo Chitman was elected as the city's first African American Mayor.

Current Mayor Marco McClendon, who became the youngest West Memphis Mayor to be sworn into office in 2019, is also African American as well.On December 14, 1987, a tornado killed six people and caused approximately $35 million in damage. The town had not recovered from the tornado damage when it flooded from 12 inches (300 mm) of rain on December 25, 1987.

Additionally, 7 to 10 inches (180 to 250 mm) of snow fell on January 6, 1988. When the snow began to melt, this added to the already existing flood problems and the destruction caused by the tornado. Some of the major employers in the city are Schneider National Carriers, Southland Park Gaming & Racing, Family Dollar Distribution, FedEx National LTL, and Robert Bosch Power Tools.

Family Dollar Distribution and FedEx National LTL are located in the Mid-America Industrial Park west of the city. The 1993 murders of three young boys and the subsequent convictions of Damien Echols, Jason Baldwin, and Jessie Misskelley, Jr. brought a lot of unwanted attention to West Memphis. The three young men convicted were known as the West Memphis Three and brought about a great amount of public intrigue.

Three documentaries have been made about the incident, the first being Paradise Lost: The Child Murders at Robin Hood Hills. Echols, Baldwin, and Misskelley were released from jail in 2011 after signing an Alford plea which allowed them to plea guilty while maintaining their innocence. They were released with time served and placed on probation until 2021.