Background: HER2 (ERBB2) gene amplification (amp) is a potential therapeutic target beyond breast and gastric cancers. HER2 amp can be detected in plasma cfDNA which may be an alternative to tissue biopsy. HERALD/EPOC1806 was a multicenter, investigator-initiated phase 2 trial of T-DXd for patients with HER2-amplified advanced solid tumors identified by cfDNA testing. Methods: We enrolled adults with advanced solid tumors harboring HER2 amp detected by next-generation sequencing of cfDNA (Guardant360) in the GOZILA study (UMIN000029315). We excluded breast or gastric cancer patients with HER2 overexpression (IHC 3+ or IHC 2+/ISH+). Patients received T-DXd 5.4 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR). Results: From December 2019 to January 2022, 4,734 patients were screened by cfDNA in the GOZILA study. Among 252 with HER2 amp, 62 with 16 cancer types were enrolled in HERALD. Median baseline plasma HER2 copy number (CN) was 8.55 (range, 2.4–73.9). All patients but 3 (all with salivary gland cancer) received prior anti-cancer therapy (median, 3 lines; range, 0–8). At a median follow-up of 8.9 months (data cut-off: July 17, 2022), the confirmed ORR was 56.5% (95% CI, 43.3–69.0%), statistically higher than the threshold value of 5%. Responses were observed for 13 cancer types, including KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric cancers (1/2). Plasma HER2 CN above vs. below the baseline median value did not impact response (ORR: 58.1% vs. 54.8%); however, the clearance vs. persistence of HER2 amp in cfDNA on Cycle 2 Day 1 corresponded to higher response (ORR: 88.0% vs. 22.7%). ORR by independent review was 58.1% (95% CI, 44.8–70.5%), and the disease control rate was 90.3% (95% CI, 80.1–96.4%). Median progression-free survival was 7.0 (95% CI, 4.9–9.7) months, and the median duration of response was 8.8 months (95% CI, 5.8–11.2). Most adverse events were mild to moderate. Interstitial lung diseases occurred in 16 patients (25.8%, G1/G2/G3; 14/1/1). Conclusions: T-DXd achieved a high ORR, durable response with a manageable safety profile in patients with advanced solid tumors and HER2 amp detected in cfDNA. Clinical trial information: JapicCTI-194707.