Entrepreneurs' changes to different business areas can be viewed as shifts in entrepreneurial knowledge domains (e.g., from restaurant to food waste processing firm as an ecological helping business). From a sample of 73 representative entrepreneurs, we present a study of the impact of such area changes on the persistence of entrepreneurship (i.e., the degree an entrepreneur remains in entrepreneurial activities). Furthermore, two mediators, managerial experience and insecurity, and two moderators, positive and negative affect, were proposed and examined to make a more comprehensive theoretical inference of the relationship between area difference and persistence. The results revealed that, counter-intuitively, area difference was significantly and positively associated with entrepreneurial persistence. The mediation effects of managerial experience and psychological insecurity were also confirmed. However, only the moderation of positive affect was effective. Based on the knowledge heterogeneity and entrepreneurial emotion perspectives, academic and practical implications for inter-temporal dynamics of entrepreneurship are discussed.