Background Grain yield is a complex and polygenic trait influenced by the photosynthetic source-sink relationship in wheat. The top three leaves, especially the flag leaf, are considered the major sources of photo-assimilates accumulated in the grain. Determination of significant genomic regions and candidate genes affecting flag leaf size can be used in breeding for grain yield improvement. Results With the final purpose of understanding key genomic regions for flag leaf size, a meta-analysis of 521 initial quantitative trait loci (QTLs) from 31 independent QTL mapping studies over the past decades was performed, where 333 loci eventually were refined into 64 meta-QTLs (MQTLs). The average confidence interval (CI) of these MQTLs was 5.28 times less than that of the initial QTLs. Thirty-three MQTLs overlapped the marker trait associations (MTAs) previously reported in genome-wide association studies (GWAS) for flag leaf traits in wheat. A total of 2262 candidate genes for flag leaf size, which were involved in the peroxisome, basal transcription factor, and tyrosine metabolism pathways were identified in MQTL regions by the in silico transcriptome assessment. Of these, the expression analysis of the available genes revealed that 134 genes with > 2 transcripts per million (TPM) were highly and specifically expressed in the leaf. These candidate genes could be critical to affect flag leaf size in wheat. Conclusions The findings will make further insight into the genetic determinants of flag leaf size and provide some reliable MQTLs and putative candidate genes for the genetic improvement of flag leaf size in wheat.