This study dealt with finding the topics perceived to be difficult in Biology by Senior School students in Isoko North Local Government Area of Delta South Senatorial District of Delta State. The researchers adopted descriptive survey research design in carrying out this study. Six research questions were formulated to guide the study. The population of the study was 904 Senior School III students. 200 (130 female and 70 male) Senior School III formed the sample. The instrument used for data collection was Student‟s Perception on the Difficult Topics in Biology. Cronbach Alpha statistic revealed that the reliability index of the instrument was 0.81. The instrument contained Biology topics as contained in West African Senior School Certificate Examinations Syllabus and Regulations, which the respondents responded to on the basis of Very Difficult, Difficult, Very Easy and Easy and rated as 4, 3, 2 and 1, respectively. The percentage statistic was used to analyse data, using 50% as the cut-off. The result of the analysis among others was that nervous coordination was perceived as the most difficult topic in Biology by both the male and female Senior School students in Isoko North Local Government Area, Delta State. Recommendations were given to improve teaching and learning strategies.