Feeding a high-fat diet (HFD) has been shown to alter phenotypic and metabolic parameters in Drosophila melanogaster. However, the impact of fat quantity and quality remains uncertain. We first used butterfat (BF) as an example to investigate the effects of increasing dietary fat content (3–12%) on male and female fruit flies. Although body weight and body composition were not altered by any BF concentration, health parameters, such as lifespan, fecundity and larval development, were negatively affected in a dose-dependent manner. When fruit flies were fed various 12% HFDs (BF, sunflower oil, olive oil, linseed oil, fish oil), their fatty acid profiles shifted according to the dietary fat qualities. Moreover, fat quality was found to determine the effect size of the response to an HFD for traits, such as lifespan, climbing activity, or fertility. Consistently, we also found a highly fat quality-specific transcriptional response to three exemplary HFD qualities with a small overlap of only 30 differentially expressed genes associated with the immune/stress response and fatty acid metabolism. In conclusion, our data indicate that not only the fat content but also the fat quality is a crucial factor in terms of life-history traits when applying an HFD in D. melanogaster.