Study purpose. Building social interactions is challenging due to difficulties in communicating clearly and adjusting to new learning systems. Because of the Covid-19 pandemic, there is a significant difficulty with this. There is a need to promote student well-being because of this unfavorable situation, which undoubtedly makes it harder to achieve. This research aimed to study the effect of interpersonal communication on students’ well-being in view of their gender in students in grades X and XI at Madrasah Aliyah Negeri 2 Banyumas, Indonesia, during learning in the pandemic period. Materials and methods. This study used the quantitative method by testing simple linear regression and t-test. The study sample comprised a total of 265 students selected using the method of proportionate stratified random sampling. The instruments in this research used the scale of student well-being with reliability of (α Cronbach = 0.835), and the scale of interpersonal communication with reliability of (α Cronbach = 0.761). Results. The results of this study showed that 1) interpersonal communication has an effect of 20.1% on the variation of students’ well-being; 2) students’ well-being for male and female students was not significantly different. The interpersonal communication between male and female students, however, differed significantly. Conclusions. Therefore, according to this research, it is essential to practice the skill of interpersonal communication in order to be able to improve students’ well-being.