Mulching is one of the most recommended practices in agriculture due to its positive effects on the plant/soil system. Very few experiments have been conducted to date to investigate the effect of mulching, with both organic and inorganic materials, on tobacco. The main aim of this study was to test the synergic effect of a soil-biodegradable (according to standard EN17033) mulching film (the commercial Mater-Bi®, Novamont SpA, Novara, Italy) and drip irrigation (M-D) compared with that of bare soil and sprinkler/drip irrigation (first/second part of the growing season; BS-SD) on a tobacco crop (Nicotiana tabacum L., flue-cured Virginia) grown in the Tiber Valley (the tobacco cultivation district of Central Italy). BS-SD represents the standard practice applied by tobacco growers in the study area. The plants grown under the M-D management system grew more and developed faster than the plants grown under BS-SD conditions. Under the M-D system, yields increased in comparison with the BS-SD conditions (+29%, on average). The gross revenue obtained via the M-D-cured products also increased (+63%, on average) thanks to higher prices assigned by expert evaluators on the basis of the extrinsic quality traits (color, structure and texture, degree of ripeness, elasticity, lamina integrity, handling defects, and vein incidence). The economic value of the cured products increased with the leaf crowns; it was the lowest in the basal (B) leaves and the highest in the middle-upper (MU) leaves. The intrinsic quality traits of the cured leaves (total N and nitrate contents, alkaloids, and reducing sugars) also confirmed that the best quality was found in the M-D-cured products, as determined by expert evaluation. Interestingly, the reducing sugar (RS) contents of tobacco obtained using the M-D management system were 2.5-, 1.1-, and 0.9-fold greater than those under the BS-SD conditions (B, M, and MU products, respectively). An additional commercial value of the cured products was thus obtained with the M-D crop management system due to RS, an intrinsic quality trait considered by manufacturing industries.