High Mobility Group A1 (HMGA1), an abundant non-histone chromatin protein, has been implicated in embryonic development1, cancer2, and cellular senescence3, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence (OIS) model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a unique 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of constitutive heterochromatic loci. This is coupled with the exclusion of HMGA1-poor chromatin regions, leading to coordinated gene regulation by repositioning genes. In the absence of HMGA1, the whole process is largely reversed, but many new regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype4 (SASP). Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar ‘buffer’ effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a fundamental HMGA1-mediated mechanism of modulating chromatin compartmentalization and gene regulation in senescence and beyond.