Broussonetia papyrifera invasion poses a serious threat to indigenous tree species in Ghana. Many conservation scientists therefore emphasize the need to control, manage, and possibly eradicate the species. However, attempts at control and management require adequate knowledge of its ecology and impact on invaded ecosystems. Employing a complete randomized design with twenty-four (24) 20 m × 20 m plots, 12 each on invaded and uninvaded sites, this study assesses the indigenous species regeneration potential under Broussonetia papyrifera-invaded sites in the Pra-Anum forest reserve. The study provides evidence of the negative impact of Broussonetia on the regenerative capacity of the reserve, as 335 seedlings per 4800 m2 distributed over 43 species were recorded on the uninvaded site compared to 156 seedlings per 4800 m2 distributed over 31 species on the invaded site. The study, however, observed some level of resilience of species belonging to the Ulmaceae and Lecythidaceae families, as they appeared fairly represented on the invaded site. Floristic diversity was also observed to be negatively impacted by Broussonetia invasion as mean Shannon and Simpson index values of 2.39 ± 0.71 and 0.89 ± 0.08 and 1.39 ± 0.24 and 0.64 ± 0.08 were recorded on the uninvaded and invaded sites, respectively. Furthermore, the Broussonetia invasion compromised the productivity of the forest ecosystem as 4.9 ± 1.61 mean economic tree species per 400 m2 plot were recorded on the invaded site compared to 13.8 ± 1.28 per 400 m2 plot on the uninvaded site. The study, therefore, concludes that Broussonetia invasion poses a serious threat to the integrity and productivity of the Pra-Anum forest reserve. Consequently, the study recommends the control of the spread of the species to protect the integrity of the Pra-Anum forest reserve. Also, restoration efforts in invaded areas of the reserve could consider the use of native species belonging to the Ulmaceae and Lecythidaceae families as they appear to be resilient to Broussonetia invasion.