Purpose <p>Hepatic arterial infusion pump (HAIP) therapy is a promising treatment for metastatic colorectal cancer (mCRC) with liver metastases, delivering targeted therapy to improve efficacy and reduce systemic toxicity. This retrospective study evaluates HAIP outcomes at an academic center and safety net hospital.</p> Methods <p>Patients with mCRC and liver metastases receiving at least one HAIP floxuridine (FUDR) cycle in combination with systemic chemotherapy (SCT) from 2013 to 2023 were included. Baseline data on demographics, tumor characteristics, and prior treatments were collected. The primary outcome was overall survival (OS) post-pump placement, with secondary outcomes of real-world progression-free survival (rwPFS) —defined as the time from HAIP placement to radiographic disease progression or death— and HAIP-related complications.</p> Results <p>Of 88 patients assessed, 63 met inclusion criteria. Median age was 46 years (IQR 41–57); 54% were male. Prior to HAIP, 60% (<i>n</i> = 38) received one line of systemic chemotherapy (SCT), and 29% (<i>n</i> = 18) received two. Median OS was 38.0 months (95% CI 21.9–not reached), and median rwPFS was 11.2 months (95% CI 7.1–16.1). Univariate analysis linked baseline bilirubin, KRAS mutation, and CEA levels to OS. However, only elevated baseline bilirubin remained an independent predictor of worse survival in the final multivariate model. Common complications were hematoma (6.4%, <i>n</i> = 4) and pump infection (3.2%, <i>n</i> = 2). Grade 3 FUDR toxicities were rare: elevated alkaline phosphatase (<i>n</i> = 6), AST/ALT (<i>n</i> = 3), bilirubin (<i>n</i> = 2), and thrombocytopenia (<i>n</i> = 1).</p> Conclusions <p>HAIP treatment with FUDR is an effective treatment option for patients with mCRC and hepatic metastasis. HAIP treatment is associated with enhanced survival outcomes and limited rates of complications. Prospective, randomized studies are needed to confirm HAIP’s role in mCRC management.</p>