Objective <p>Ondansetron oral soluble pellicles (OSP) show satisfactory effects on preventing nausea and vomiting following antitumor therapies. This study aimed to compare the antiemetic efficacy and safety profiles of ondansetron OSP vs. azasetron in patients receiving antitumor therapies.</p> Methods <p>A total of 110 patients who received antitumor therapies were included in this comparative observational study. According to patient willingness, disease status, and tolerance, 55 patients received ondansetron OSP, and the other 55 patients received intravenous azasetron. During acute and delayed phases, the function living index emesis (FLIE) scale score and degrees of nausea and vomiting [high (46–63 points), moderate (19–45 points), or low (0–18 points)] were assessed. Adverse reactions were collected.</p> Results <p>During the acute phase, FLIE-nausea (5.7 ± 8.9 vs. 17.9 ± 13.6) and vomiting (6.9 ± 7.8 vs. 17.6 ± 13.9) domain scores were lower in patients receiving ondansetron OSP than those receiving azasetron (both <i>P</i> &lt; 0.001). The degrees of nausea and vomiting were lower in patients receiving ondansetron OSP than those receiving azasetron (both <i>P</i> &lt; 0.05). During the delayed phase, FLIE-nausea (5.0 ± 7.9 vs. 10.8 ± 9.1) and vomiting (4.2 ± 6.6 vs. 9.2 ± 8.7) domain scores were lower in patients receiving ondansetron OSP than those receiving azasetron (both <i>P</i> &lt; 0.001). Regarding adverse reactions, the incidence of constipation was lower in patients receiving ondansetron OSP than those receiving azasetron (7.3% vs. 30.9%) (<i>P</i> = 0.003), but the incidence of headache did not differ (<i>P</i> = 0.113).</p> Conclusion <p>Ondansetron OSP possess superior antiemetic effects and safety profiles to azasetron in patients receiving antitumor therapies.</p>