North American populations ofDrosophila melanogasterderive from both European and African source populations, but despite their importance for genetic research, patterns of ancestry along their genomes are largely undocumented. Here, I infer geographic ancestry along genomes of theDrosophilaGenetic Reference Panel (DGRP) and theD. melanogasterreference genome, which may have implications for reference alignment, association mapping, and population genomic studies inDrosophila.Overall, the proportion of African ancestry was estimated to be 20% for the DGRP and 9% for the reference genome. Combining my estimate of admixture timing with historical records, I provide the first estimate of natural generation time for this species (approximately 15 generations per year). Ancestry levels were found to vary strikingly across the genome, with less African introgression on the X chromosome, in regions of high recombination, and at genes involved in specific processes (e.g., circadian rhythm). An important role for natural selection during the admixture process was further supported by evidence that many unlinked pairs of loci showed a deficiency of Africa-Europe allele combinations between them. Numerous epistatic fitness interactions may therefore exist between African and European genotypes, leading to ongoing selection against incompatible variants. By focusing on hubs in this network of fitness interactions, I identified a set of interacting loci that include genes with roles in sensation and neuropeptide/hormone reception. These findings suggest that admixedD. melanogastersamples could become an important study system for the genetics of early-stage isolation between populations.