The obesity epidemic has become a major public health concern globally, and the food supply is a significant driver of this trend. Front-of-package (FOP) labels have been implemented in many countries to encourage healthier food choices. This systematic review aimed to examine the effect of FOP label implementation on food manufacturers’ practices. A comprehensive search of multiple databases was conducted following PRISMA guidelines, identifying 39 relevant articles from 1990 to 2021. The studies indicated that FOP labels conveying intuitive information influenced product reformulation, whereas those with numerical information without specific guidance had no impact on reducing unhealthy nutrients. The most common outcomes were sodium, sugar, and calorie reduction. Mandatory policies reported higher and more consistent effects on product reformulation compared to voluntary approaches. Voluntary FOP labeling resulted in low uptake and tended to be applied to healthier products. Food manufacturers responded to FOP labeling heterogeneously, depending on the label design and type of enforcement. FOP label implementation can reduce nutrients of concern but food manufacturers behave strategically by labeling healthier choices. This review provides recommendations for maximizing the benefits of using FOP labels to prevent obesity, and findings can inform future public health research and policymaking.