Background: In patients with unresectable liver-confined CRLM, regional chemotherapy via HAI in combination with modern systemic chemotherapy (CT) can achieve hepatic disease control and expand surgical resectability. We describe patient selection and early outcomes following implementation of a HAI program at our tertiary referral academic center. Methods: We analyzed demographics, previous systemic treatment, primary tumor location, molecular profiling, extent of hepatic/extrahepatic disease, perioperative HAI outcomes (toxicity, conversion to resection/ablation, radiographic response), and overall survival (OS) in CRLM patients selected for HAI treatment (01/2018—06/2020) after multidisciplinary review. Results: Of 35 patients with unresectable CRLM (primary: colon, n = 24; rectum, n = 11) selected for HAI, 57% were heavily pre-treated (with at least 2 lines of pre-HAI systemic chemotherapy), 71% had a Fong clinical risk score ≥3, 86% presented with synchronous disease, 80% had bilobar metastasis, and 86% had > 5 tumors. All tumors were microsatellite stable, with 20% harboring KRAS/NRAS mutations and none had class I/II BRAF mutations. HAI was initiated at a median 14 (IQR 3, 64) months after CRLM diagnosis, and administered for a median of 7 (range 2, 16) cycles; 91% of patients (31/34) received concurrent HAI and systemic chemotherapy. Although most (69%) patients experienced some degree of hepatic toxicity during HAI therapy resulting in FUDR dose reduction and steroid administration, biliary sclerosis requiring intervention was observed in only 3 (9%) of patients. The overall perioperative morbidity was 17%, and there were no surgical-related 90-day mortalities following HAI pump placement. Excluding patients who initiated HAI treatment within the last 3 months of the study period (n = 3), 13 of 32 patients (41%) were rendered disease-free in the liver following complete resection and/or ablation in combination with HAI/systemic chemotherapy; in the remaining 19 patients (59%), hepatic progression-free survival was 7.3 months (IQR 4, 12). At a median follow-up of 11.2 months, post-HAI median OS for the overall cohort was 12.3 (IQR 7, 20) months. Patients undergoing complete resection/ablation demonstrated improved survival compared with those with progressive disease (median 20 vs 12 months, respectively). Conclusions: Implementation of a HAI program for multimodality liver-directed management of unresectable CRLM is feasible and is associated with meaningful clinical outcomes unlikely to be achieved with systemic therapy alone in heavily pre-treated patients.