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Abstract Neutrophil extracellular traps (NETs) have been implicated in the pathology of various inflammatory conditions. In cancer, NETs have been demonstrated to induce systemic inflammation, impair peripheral vessel and organ function and promote metastasis. Here we show that the plasma level of NETs is significantly higher in patients with metastatic breast cancer compared to those with local disease, or those that were considered cured at a 5‐year follow‐up, confirming NETs as interesting therapeutic targets in metastatic breast cancer. Administration of DNase I is one strategy to eliminate NETs but long‐term treatment requires repeated injections and species‐specific versions of the enzyme. To enhance administration and therapeutic efficacy, we have developed an adeno‐associated virus (AAV) vector system for delivery of murine DNase I and addressed its potential to counteract cancer‐associated pathology in the murine MMTV‐PyMT model for metastatic mammary carcinoma. The AAV vector is comprised of capsid KP1 and an expression cassette encoding hyperactive murine DNase I (AAV‐mDNase I) under the control of a liver‐specific promotor. This AAV‐mDNase I vector could support elevated expression and serum activity of murine DNase I over at least 8 months. Neutrophil Gelatinase‐Associated Lipocalin (NGAL), a biomarker for kidney hypoperfusion that is upregulated in urine from MMTV‐PyMT mice, was suppressed in mice receiving AAV‐mDNase I compared to an AAV‐null control group. Furthermore, the proportion of mice that developed lung metastasis was reduced in the AAV‐mDNase I group. Altogether, our data indicate that AAV‐mDNase I has the potential to reduce cancer‐associated impairment of renal function and development of metastasis. We conclude that AAV‐mDNase I could represent a promising therapeutic strategy in metastatic breast cancer.