The mapping and introduction of sustainable plant immunity to pests and diseases in fruit tree is still a major challenge in modern breeding. This study aims at deciphering the genetic architecture underlying resistance or tolerance across environments for major pests and diseases in peach ( P. persica ) and apricot ( P. armeniaca ). We set up a multi-environment trial (MET) approach by studying two core collections of 206 peach and 150 apricot accessions deployed under low phytosanitary conditions in respectively three and two environmentally contrasted locations in South-East of France. To capture the complex dynamics of pest and disease spread in naturally infected orchards, visual scoring of symptoms was repeated within and between 3 years, for five and two pests and diseases respectively for peach and apricot, resulting in the maximum of damage score and the AUDPC. These traits were used as phenotypic inputs in our genome-wide association studies (GWAS) strategy, and leading to the identification of: i) non-additive genotype–phenotype associations, ii) environment-shared QTLs iii) environment-specific QTLs, and iv) interactive QTLs which changes in direction (‘antagonist’) or intensity (‘differential’) according to the environment. By conducting GWAS with multiple methods, we successfully identified a total of 60 high confidence QTLs, leading to the identification of 87 candidate genes, the majority belonging to the Leucine-rich repeat containing receptors (LRR-CRs) family gene. Finally, we provided a comparative analysis of our results on peach and apricot, two closely related species. The present results contribute to the development of genomics-assisted breeding to improve biotic resilience in Prunus varieties.