In September 2018, CDC identified Salmonella enterica serotype Newport (Newport) infections that were multidrug resistant (MDR), with decreased susceptibility to azithromycin, a recommended oral treatment agent. Until 2017, decreased susceptibility to azithromycin had occurred in fewer than 0.5% of Salmonella isolates from U.S. residents. This report summarizes the investigation of a multistate MDR Salmonella outbreak conducted by CDC, state and local health departments, and the U.S. Department of Agriculture's Food Safety and Inspection Service. During June 2018-March 2019, 255 cases of infection with the outbreak strain were identified in 32 states; 43% of patients (89 of 206 with information on travel) reported recent travel to Mexico. Infections were linked to consumption of soft cheese obtained in Mexico and beef obtained in the United States. Consumers should avoid eating soft cheese that could be made from unpasteurized milk, regardless of the source of the cheese. When preparing beef, a food thermometer should be used to ensure that appropriate cooking temperatures are reached. When antibiotic treatment is needed for a patient, clinicians should choose antibiotics based on susceptibility testing wherever possible.