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<i>Background</i>: This study aimed to investigate the clinical form, risk factors, and outcomes of patients with COVID-19 and <i>Clostridioides difficile</i> co-infections. <i>Methods</i>: This retrospective study (2 September 2021–1 April 2022) included all patients with <i>Clostridioides difficile</i> infection (CDI) and COVID-19 infection who were admitted to the Covid Hospital of the University Clinical Center of Vojvodina. <i>Results</i>: A total of 5124 COVID-19 patients were admitted to the Covid Hospital, and 326 of them (6.36%) developed hospital-onset CDI. Of those, 326 of the CDI patients (88.65%) were older than 65 years. The median time of CDI onset was 12.88 days. Previous hospitalizations showed 69.93% of CDI patients compared to 38.81% in the non-CDI group (<i>p</i> = 0.029). The concomitant antibiotics exposure was higher among the CDI group versus the non-CDI group (88.65% vs. 68.42%, <i>p</i> = 0.037). Albumin levels were ≤ 25 g/L among 39.57% of the CDI patients and 21.71% in the non-CDI patients (<i>p</i> = 0.021). The clinical manifestations of CDI ranged from mild diarrhea (26.9%) to severe diarrhea (63.49%) and a complicated form of colitis (9.81%). Regarding outcomes, 79.14% of the CDI patients recovered and 20.86% had fatal outcomes in-hospital. Although a minority of the patients were in the non-CDI group, the difference in mortality rate between the CDI and non-CDI group was not statistically significant (20.86% vs. 15.13%, <i>p</i> = 0.097). <i>Conclusions</i>: Elderly patients on concomitant antibiotic treatments with hypoalbuminemia and with previous healthcare exposures were the most affected by COVID-19 and CD co-infections.