Unprecedented quarantine due to COVID-19 exposes individuals to withdraw from face-to-face interactions, which may influence communication and self-esteem (SE). Therefore, the overarching aims of this study are to examine the communication apprehension levels among female college students, and thus to investigate the moderating role of self-esteem on the relationship between communication apprehension and academic achievement. In this cross-sectional study, 287 female college students completed the survey, which was circulated through email. The survey included the following questionnaires: General Health Characteristics, Rosenberg Self-esteem Scale, and Personal Report of Communication Apprehension Scale. The results showed that 28.2% of participants were categorized as having a high level of communication apprehension, and only 9.8% had a low level of communication apprehension. The SE reported an overall score of 24.3 ± 2.14, indicating a high self-esteem level among students. The students’ grade point average (GPA) was positively correlated with SE. However, self-esteem as a moderator variable had no significant effect on the relationships between all predictors and GPA. The finding of the study highlights the need to implement different strategies to enhance students’ group discussions, meetings, and interpersonal communication to ensure the best learning outcomes. Future studies are required to investigate gender-based disparities in the relationship between communication apprehension and SE.