Background: An initial step to reducing emergency department (ED) visits among patients with cancer is to identify the characteristics of patients visiting the ED and examine which of those visits could be prevented. The objective of this study was to explore nationwide trends and characteristics of ED visits and examine factors associated with potentially preventable ED visits and unplanned hospitalizations among patients with cancer in the US. Methods: This cross-sectional study used data on ED visits from the National Hospital Ambulatory Medical Care Survey from January 1, 2012, to December 31, 2019; US Cancer Statistics reports were used to estimate new cancer cases each year. Frequencies and trends of ED visits by adult patients (aged ≥18 years) with cancer were calculated. The primary outcome was potentially preventable ED visits (using the Centers for Medicare & Medicaid Services definition), and secondary outcomes were hospitalizations and the immediacy of the ED visits. Multivariable logistic regression analyses were performed to examine the associations of patient, hospital, and temporal factors with potentially preventable ED use and ED use resulting in hospitalization. Results: Among 854911106 ED visits, 35510014 (4.2%) were made by patients with cancer (mean [SD] age, 66.2 [16.2] years); of those, 55.2% of visits were among women, 73.2% were among non-Hispanic White individuals, 89.8% were among patients living in a private residence, and 54.3% were among Medicare enrollees. A total of 18 316 373 ED visits (51.6%) were identified as potentially preventable, and 5 770 571 visits (21.3%) were classified as high acuity. From 2012 to 2019, potentially preventable ED visits increased from 1 851 692 to 3 214 276. Pain (36.9%) was the most common reason for potentially preventable ED visits. The number of patients who visited an ED because of pain increased from 1 192 197 in 2012 to 2 405 849 in 2019 (a 101.8% increase). Overall, 28.9% of ED visits resulted in unplanned hospitalizations, which did not change significantly over time (from 32.2% in 2012 to 26.6% in 2019; P = .78 for trend). Factors such as residence in a nursing home (odds ratio, 1.73; 95% CI, 1.25-2.41) were positively associated with having a potentially preventable ED visit, and factors such as the presence of more than 1 comorbidity (odds ratio, 1.82; 95% CI, 1.43-2.32) were positively associated with having an unplanned hospitalization. Conclusions: In this study, 51.6% of ED visits among patients with cancer were identified as potentially preventable, and the absolute number of potentially preventable ED visits increased substantially between 2012 and 2019. These findings highlight the need for cancer care programs to implement evidence-based interventions to better manage cancer treatment complications, such as uncontrolled pain, in outpatient and ambulatory settings.