Cassava cultivation causes serious soil fertility depletion in southern Cameroon due to high mining of soil nutrients by the crop. This study aimed to evaluate the effects of Tithonia diversifolia fresh biomass (TB), poultry manure (PM) and inorganic fertilizers (IF) on soil properties, cassava yield, and the economic returns. The treatments consisted of two rates of TB (10 and 20 t ha−1), two rates of PM (10 and 20 t ha−1), two rates of combined TB and PM (5 and 10 t ha−1), a single rate of inorganic fertilizers (100 N:22P:83 K kg ha−1) and a control. The results showed that soil properties, soil quality index and cassava yield were significantly improved by the application of the organic manures. Tithonia diversifolia fresh biomass (TB) and poultry manure (PM) lowered the soil bulk density, increased soil total porosity, water holding capacity and chemical properties. TB and PM, solely or mixed, improved the aerial dry biomass (ADB) and fresh tuber yield (FTY) of cassava. The organic manures performed better than inorganic fertilizer. The highest yield (51 and 52 t ha−1 of fresh tubers) was obtained with the mixture of TB and PM applied at 10 t ha−1 each for the successive years. Positive and significant correlation was found between SQI and cassava yield. TB and PM combined at 10 t ha−1 each was the most profitable and cost-effective treatment, with a good benefit:cost ratio of 3.2:1 and net return of FCFA 3.736.900 ha−1. Thus, the use of Tithonia diversifolia fresh biomass and poultry manure is a sustainable method for cassava production in the southern Cameroon.