Pellets, reliant on pH-sensitivity and time-dependency for drug delivery, provide one of the most versatile opportunities for targeting colon. 5-Fluorouracil (5-FU) loaded pellets were prepared by extrusion-spheronization using Avicel(®) PH101 as a spheronization aid and hydroxypropylmethylcellulose K4M (HPMC K4M) solution as a binder. A 3(2) full factorial design was employed to optimize spheronization speed and time. Obtained pellets were evaluated for flow properties, pellet size, roundness and aspect ratio. Optimized batch was coated in a bottom-spray fluidized bed processor (FBP) with an inner coat of sustained release polymer Eudragit NE30D and an outer coat of pH-sensitive polymer Eudragit FS30D. The coating levels were statistically optimized and in vitro drug release was monitored by changing pH media method. Optimized system with 15% inner and outer coating levels revealed t(50%) (time required for 50% drug release) to be about 9 h while almost complete drug was released in 24 h (98.71 ± 1.33%) with highest dissolution efficiency (DE(24h)) of 58.71%. The optimization model was validated; the predicted and experimental/actual values for validation batch (M1) were in close tolerance and the standard error (SE) was also small. Drug release was also studied at pH 7.4. Scanning electron microscopy (SEM) demonstrated average coating thickness to be 32.50 ± 3.0 µm. Hence, the present study provides constructive results for colon targeting of 5-FU pellets with industrially feasible processes.