Small open reading frames (sORFs) can encode functional “microproteins” that perform crucial biological tasks. However, their size makes them less amenable to genomic analysis, and their origins and conservation are poorly understood. Given their short length, it is plausible that some of these functional microproteins have recently originated entirely de novo from noncoding sequences. Here we sought to identify such cases in the human lineage by reconstructing the evolutionary origins of human microproteins previously found to have measurable, statistically significant fitness effects. By tracing the formation of each ORF and its transcriptional activation, we show that novel microproteins with significant phenotypic effects have emerged de novo throughout animal evolution, including two after the human-chimpanzee split. Notably, traditional methods for assessing coding potential would miss most of these cases. This evidence demonstrates that the functional potential intrinsic to sORFs can be relatively rapidly and frequently realized through de novo gene emergence. Display omitted •We estimate the evolutionary origins of functional human microproteins•Some are novel, having originated entirely de novo from noncoding sequences•These mostly lack sequence signals of conservation and selection•Many more novel ones could exist and escape detection Human microproteins encoded by small ORFs have been found to be functional. By comparing the corresponding sequences across vertebrate genomes, Vakirlis et al. show that a number of these originated “from scratch” from noncoding sequences, including two very recent cases unique to humans. These cases demonstrate the rapid evolution of genetic novelty.