Wine is an alcoholic beverage produced worldwide dominantly from a grape. In Ethiopia, the post-harvest loss of agricultural products is tremendous that estimated from 20-50%. Thus, the objective of this research was to produce wine from different blending ratios of sugar cane & guava juice, to characterize the product, and to optimize the process. The design was executed by lower and upper levels of sugar cane:guava juice blending ratio (BR) of 80%:20% and 60%:40%, fermentation temperature (T) of (20-30ºC, fermentation time (t) of 7-13 days for both red and white guava variety. The optimization was carried out using Optimal Custom Design. The physicochemical, sensory properties, and microbial quality were determined. All analyses were subjected to ANOVA (analysis of variance) to obtain the significant difference between the mean values using LSD (p < 0.05) using Minitab version 19. The raw material grape, sugar cane, red guava, and white guava have ºbrix of (14.0, 20.0, 8.0, and 10.0) pH of (4.18, 5.12, 4.25, and 4.35) vitamin C content of (36.59, 21.19, 219.80 and 256.00mg/100ml) respectively. The total bacteria growth were ranged from 4.61 to 6.80 log (CFU/ml) where as the yeast and mold were ranged from 2.43 to 5.90 log (CFU/ml). Optimum process parameters of blending ratio of 60:40 for both guava varieties, fermentation temperature of 26.4ºC &26.1ºC, and fermentation time of 10.08 & 9.96 days were obtained for sugar cane-red and white guava blend wine respectively. At this optimum condition titratable acidity, Vitamin c, total phenol and alcohol content of 0.568% , 24.92 mg/100ml , 3.28 mg/l & 12.3%v/v and 0.566%, 38.02mg/100ml, 3.98mg/l &12.2%v/v were produced for sugar cane-red and white guava blend wine, respectively. There was a low percentage error for both sugar cane-red and white guava blend wine. The percentage of error ranged from 0.7 to 3.2% and 1.4 to 5.4% for sugar cane–red and white guava blend wine respectively Keywords: Grape, Guava, Postharvest, Sensory Property, Optimization, Physicochemical Property, Sugar Cane, Wine