The analysis of gene sets is usually carried out based on gene ontology terms and known biological pathways. These approaches may not establish any formal relation between genotype and trait specific phenotype. In plant biology and breeding, analysis of gene sets with trait specific Quantitative Trait Loci (QTL) data are considered as great source for biological knowledge discovery. Therefore, we proposed an innovative statistical approach called Gene Set Analysis with QTLs (GSAQ) for interpreting gene expression data in context of gene sets with traits. The utility of GSAQ was studied on five different complex abiotic and biotic stress scenarios in rice, which yields specific trait/stress enriched gene sets. Further, the GSAQ approach was more innovative and effective in performing gene set analysis with underlying QTLs and identifying QTL candidate genes than the existing approach. The GSAQ approach also provided two potential biological relevant criteria for performance analysis of gene selection methods. Based on this proposed approach, an R package, i.e., GSAQ ( https://cran.r-project.org/web/packages/GSAQ ) has been developed. The GSAQ approach provides a valuable platform for integrating the gene expression data with genetically rich QTL data.