MacKenzie transited the Panama Canal 1 March 1943, after completion of shakedown and training cruises, and continued on to spend her entire World War II career in the Atlantic and Mediterranean theaters.

On 9 July she departed the north African coast, arriving at Scoglitti, Sicily, the next day to screen the transport vessels and provide fire support.

On 18 March 1944, MacKenzie steamed into the harbor at Naples to report for screening, fire support and antisubmarine patrol duties in conjunction with the Anzio operation.

Starting her Anzio assignments with an assist in the sinking of a two-man submarine on the 19th, she continued to provide support on this front until resuming convoy duties 6 June.

The destroyer took up duty in the Mediterranean again in February 1945 and from 28 March through 21 April spent her days in the bombardment of the Franco-Italian border and her nights on the blockade of the Gulf of Genoa.