Why do federal arrangements become extinct, and how? In Africa, the conventional expectation is that this would come about through overthrows of the constitution such as through coup d’états. However, using a not-so-well-known federal experiment in Ghana, this study demonstrates gradual “defederalization” through various constitution reviews across sixty-three years. Using evidence from diverse documentary sources and combining gradual change with critical juncture/path-dependence analyses, the study shows that the abolishment of regional autonomies in 1959 was possible, despite constitutional safeguards, because of political developments that weakened veto possibilities for defenders of the constitution’s quasi-federal features. Subsequently, defenders of federalism missed an opportunity in 1968 to reinstate those features, which consequently sealed the fate of Ghana’s federal experiment and has led to defunct regional autonomy. With this insight, the findings call attention to endogenous change mechanisms as key to understanding the path-dependent evolution of federal systems in Africa.