Background Endoscopic dacryocystorhinostomy (EN-DCR) is an increasingly common procedure performed by otolaryngologists. While EN-DCR has a high rate of success at relieving blockage of the lacrimal system, little is known regarding associated postoperative infection (POI) rates and risk factors. Objective The purpose of this study was to identify factors associated with the occurrence of postoperative orbital and rhinologic infection in a large cohort of patients undergoing EN-DCR. Methods A retrospective review of 582 patients who underwent EN-DCR was performed. All patients received antibiotic prophylaxis as a single intraoperative intravenous administration and a ten-day postoperative oral course. Clinical and demographic information was reviewed, including the occurrence of acute orbital or rhinologic infection within 30 days of surgery. Multivariable analysis was performed to identify risk factors associated with POI. Results Fifteen of 582 patients (2.6%) developed POI following EN-DCR. The most common POI was acute rhinosinusitis (10/15, 66.7%), followed by acute dacryocystitis (2/15, 13.3%), preseptal cellulitis (2/15,13.3%), and acute bacterial conjunctivitis (1/15, 6.7%). The majority of patients (464/582, 79.7%) underwent concurrent endoscopic sinus surgery (ESS). In most cases (302/464, 65.1%), ESS was performed to address comorbid rhinosinusitis, whereas 7.8% (36/464) of patients underwent surgery to enhance surgical access to the lacrimal sac. Patients who underwent concurrent ESS were less likely to develop POI (OR: 0.17, CI: 0.04-0.80, p < 0.05). Evidence of mucopurulence at surgery increased the likelihood of POI (OR: 6.24, CI: 1.51-25.84, p < 0.05). Conclusion Mucopurulence at the time of surgery significantly increased the risk of POI, whereas concurrent ESS, performed most commonly to address comorbid rhinosinusitis, significantly decreased the risk of POI. Awareness of risk factors for POI and appropriate surgical management of concurrent rhinosinusitis can lead to reduced infectious complications after EN-DCR.