A good number of instructional strategies are identified to help students overcome their learning difficulties in the mole concept. However, Ghanaian senior high school students continue to have difficulties in the mole concept. Hence, there was the need to examine the perceived nature of learning the mole concept in the perspectives of male and female students. An explanatory sequential mixed methods design was adopted to collect quantitative and qualitative data. The students, selected through a multistage sampling procedure from four schools, responded to questionnaire and interview guide. Through independent samples t-test statistics it was established that though students were full of uncertainty about the perceived nature of the mole concept that of males differed from their female counterparts. Hence, chemistry teachers should create learning environment conducive enough for male and female students to overcome their uncertainty in the mole concept.