Cistanche deserticola is a holoparasitic plant of the Orobanchaceae family, parasitizing the roots of Haloxylon ammodendron. The absence of a high-quality genome has impeded understanding of C. deserticola's parasitic mechanisms. We present a chromosome-level assembly of C. deserticola (6.26 Gb) using PacBio HiFi and Hi-C sequencing, with an 81.25 Mb contig N50 and 92.2% BUSCO completeness, encoding 54,640 protein-coding genes. Evolutionary analysis shows that C. deserticola diverged from related Orobanchaceae species approximately 38.23 million years ago. Key parasitic adaptations include extensive photosynthetic gene loss, compensated by retained transporters and carbon metabolic pathways for host nutrient utilization. Bidirectional genetic exchanges include 34 H. ammodendron-derived horizontally transferred (HGT) genes and 98 mobile mRNAs, alongside 14 C. deserticola-derived HGT genes and 77 mobile mRNAs targeting host defenses. Spatial transcriptomic data reveal haustorium-specific expression specializing in nutrient extraction and chemical defense, particularly phenylethanoid glycosides (PhGs) biosynthesis via dispersed duplication-driven gene expansion. This genomic resource illuminates the evolutionary trajectory of C. deserticola and provides a foundation for conservation strategies and biotechnological development of C. deserticola.