A combination of by-products was studied in fresh handmade pasta. Pomegranate peels and olive oil by-products were used in the range 0–6% (w/w) and properly combined in a total of nine combinations with an equal amount of broccoli by-products (10% w/w). The broccoli by-products were added to improve the sensory acceptance, which was compromised when the two above by-products were added to the dough. To verify the synergic effects, among these by-products, on tagliatelle shelf life, microbiological quality based on the main spoilage groups, sensory properties, appearance of visible molds, pH and moisture content were monitored in all the packaged samples stored at 4 °C. In addition to fortified pasta samples, control tagliatelle was also investigated. A mathematical approach was used to fit experimental data and calculate pasta shelf life. In addition, a mathematical model was also proposed to describe the dependence of the shelf life from each by-product percentage added to the formulation. Results showed that while the control fresh pasta lasted about 3 days for the undesired proliferation of yeasts and coliforms, all fortified samples maintained acceptable quality for at least one week. Depending on the by-product combination, shelf-life values could reach more than 13 days. The best combination of by-products calculated based on the mathematical model, that reached the highest shelf life (13.30 days), corresponded to 10% broccoli by-products combined with 6% olive oil by-products and 6% pomegranate peels.