Background Exclusive Breastfeeding (EBF) for the first six months of life is globally accepted as the preferred method for infant feeding. In Ghana, an estimated 84% of children < 2 months old are exclusively breastfed. But by age 4 to 5 months, only 49% continue to receive EBF. This situation continues to deteriorate. Thus, the need to explore perceptions, practices as well as factors that influence EBF in Ghana. Methods Using a qualitative design, four focus group discussions were conducted among first-time mothers and eight in-depth interviews with health workers and traditional birth attendants. The study was conducted in four communities in the Kassena-Nankana municipality of Ghana. Discussions and interviews were recorded and later transcribed verbatim to English language. The transcribed data was then coded with the aid of analysis computer software (Nvivo version 10.0) and later analyzed for the generation of themes. Results Exclusive breastfeeding is practiced among first-time mothers due to its perceived benefits; which include nutritional advantage, ability to enhance growth whilst boosting immunity and its economic value. However misconceptions as well as, certain cultural practices (e.g. giving herbal concoctions, breastmilk purification rites), and relational influences, may threaten a mother’s intention to exclusively breastfeed. Relational influences are mainly from mother in-laws, traditional birth attendants, grandmothers, herbalists and other older adults in the community. Conclusions Although first time mothers attempt EBF, external influences make it practically challenging. The availability and utilization of information on EBF was found to positively influence perceptions towards EBF, leading to change in attitude towards the act. Thus, the practice of community-based health services may be strengthened to provide support for first-time mothers as well as continuous education to the mother in laws, female elders and community leaders who influence decision making on breastfeeding of infants