As the pioneer of the Green Revolution in China, Guangdong province witnessed the improvement and spread of semi-dwarf Xian/Indica rice cultivars and possessed diverse rice germplasm of landrace and cultivars. A total of 517 accessions containing a core germplasm of 479 newly sequenced landraces and modern cultivars were used to reveal breeding signatures and key variations for regional genetic improvement of indica rice from Guangdong. Four subpopulations were identified in the collection, which including Ind IV as a novel subpopulation that not covered by previously released accessions. Modern cultivars of subpopulation Ind II were inferred to have less deleterious variations, especially in yield related genes. About 15 Mb genomic segments were identified as potential breeding signatures by cross-population likelihood method (XP-CLR) of modern cultivars and landraces. The selected regions spanning multiple yield related QTLs (quantitative trait locus) which identified by GWAS (genome-wide association studies) of the same population, and specific variations that fixed in modern cultivars of Ind II were characterized. This study highlights genetic differences between traditional landraces and modern cultivars, which revealed the potential molecular basis of regional genetic improvement for Guangdong indica rice from southern China.