The study explores the interrelationship between innovation practices and business sustainability among indigenous entrepreneurs in Northern Ghana. The research adopted a mixed-methods design involving 250 survey responses and 15 qualitative interviews. Two key objectives guided the investigation: Examining the nature and characteristics of indigenous entrepreneurship in Northern Ghana and analysing the linkage between innovation and sustainability. Empirical findings indicate that product, process, marketing, organizational, and eco-innovations significantly influence business sustainability, with product innovation emerging as the most impactful predictor (B = 0.182, p = 0.001). The study also confirms a strong positive relationship between innovation practices and sustainability outcomes (B = 0.624, p < 0.001), explaining 30.1% of the variance.