Background: Due to COVID-19, social distancing initiatives have been enacted, highlighting differences of social distancing practices and the resulting loneliness in various populations, especially in those with a history of cancer (survivors and those in active treatment).The objective of this study was to examine whether social distancing practices and loneliness differ between individuals with and without a history of cancer during the COVID-19 pandemic. Methods: This study is part of the “Impact of COVID-19 on Behaviors across the Cancer Control Continuum in Ohio” project conducted from June to November 2020. Participants from previous studies (N = 32,989) who had given permission to be re-contacted were invited to complete a survey online, by phone, or by mail. For the current analysis, participants who had complete data on history of cancer diagnosis, COVID social distancing behaviors (staying at home, not having visitors, staying 6 feet apart, wearing a masking indoors, and wearing a mask outdoors), attendance at social gatherings, contact with people outside of their household, and feelings of loneliness were included. Linear and logistic regression models were used to determine the associations between demographics, cancer history, social distancing, and loneliness. Results: Among the eligible participants (n = 5729), 54.9% had a cancer history (n = 3147), while 45.1% did not have a cancer history (n = 2582). The average age was 56.7 years, 35.6% were male, 89.4% were White, 74.7% were partnered, and 74.5% lived in metro counties. Out of all individuals, 69.3% participated in ≥4 of the 5 COVID social distancing behaviors, 31.5% did not attend any social gatherings, and 40.1% reported feeling lonely. Compared to individuals without a cancer history, individuals with a cancer history were more likely to contact no one outside of the household (49.0% vs. 41.9%, p < 0.01) and less likely to report feeling lonely (35.8% vs. 45.3%, p < 0.01). Among individuals with a cancer history, compared to their counterparts, those who were older, Black, Asian, and living in metro counties were adherent to more social distancing behaviors (mean differences = 0.02, 0.62, 0.71, 0.13, respectively, p all < 0.05) and attended fewer social gathering (mean differences = -0.01, -0.29, -0.49, -0.12, respectively, p all < 0.05). Higher adherence to social distancing behaviors was associated with higher odds of loneliness among individuals with (OR = 1.27, 95% CI: 1.72-1.38) and without a cancer history (OR = 1.15, 95% CI: 1.06-1.25). Conclusions: Social distancing practices and loneliness during the COVID-19 pandemic varied between individuals with and without a cancer history. These findings can inform efforts to support and address all aspects of health among individuals susceptible to loneliness during the pandemic, especially those with a history of cancer.