Homologous recombination deficiency (HRD) is a clinically relevant biomarker that predicts sensitivity to PARP inhibitors and enables personalized cancer therapy. Validated local HRD testing solutions are essential to ensure timely and equitable access, ultimately improving treatment outcomes. We evaluated a shallow whole-genome sequencing (sWGS) approach for genomic instability (GI) assessment combined with a 52-gene targeted panel in ovarian cancer. Validation used reference materials and 24 archival samples with prior HRD characterization, comparing performance with the Myriad myChoice^® HRD test. A prospective cohort of 124 newly diagnosed ovarian cancer patients was then analyzed. sWGS-derived GI status showed strong concordance with the reference test (95.8% overall agreement; κ = 0.913; NPV 100%, PPV 93.3%). Pathogenic BRCA1/2 variants were detected in 30 patients (24.19%). An additional 22.76% were BRCA1/2-negative but GI-positive, giving an overall HRD prevalence of 47.15%. Platinum sensitivity occurred in 90.0% (18/20) of HRD-positive patients with follow-up. Among 12 patients assessed for PARP-inhibitor response, the overall response rate was 66.7% (95% CI 39.1–86.2) and disease control rate 83.3% (95% CI 55.2–95.3). TP53 alterations were most frequent (62.90%), followed by BRCA1 (19.35%) and BRCA2 (4.83%). Pathogenic variants in other HR-pathway genes (ATM, CHEK2, BRIP1, RAD51C, BARD1) appeared in 9.57% of BRCA-wild-type cases, with heterogeneous GI impact. Two cases showed concurrent BRCA2 variants and microsatellite instability, indicating possible eligibility for anti-PD-1/PD-L1 therapy in addition to PARPi. This first comprehensive analysis of Romanian ovarian cancer patients suggests that integrating sWGS-based genomic instability assessment with BRCA testing can improve HRD detection and reflects the heterogeneity of HR-pathway variants. Preliminary clinical observations were consistent with known HRD-associated treatment responses, although larger studies are needed to confirm these findings.