The study examined the integration of 21st Century Skills into teaching of Social Studies among public junior high school learners in Effutu Municipality in Ghana. The study adopted Pedagogical Content Knowledge theory by Shuman (1987). The positivist paradigm was followed in the conduct of the study where quantitative data was collected and analysed. The Census sampling technique was used to select all the 50 Social Studies teachers even though 45 were correctly filled and therefore used for the study. Structured questionnaires were used as instruments for data collection. With the aid of the Version 20 of the Statistical Product for Service Solution (SPSS), descriptive statistics (mean, standard deviation, frequency counts, simple percentages) and inferential statistical tools such as Ordinary Least Square multiple regression analysis was used to analyse the data. The findings of the study revealed that communication and collaboration as well as digital literacy skills had very good integration whereas creativity and innovation, cultural identity and global citizenship, personal development and leadership and critical thinking and problem-solving skills registered good integration. It further showed that 21st Century Skills mentioned above accounted for 63.8% variance in learners’ academic performance. It was recommended that Ghana Education Service should initiate and encourage continuous professional development programmes for teachers in the Effutu Municipality to improve their integration of 21st Century skills and enhance teaching and learning.