The biological control of fungal crop diseases based on the use of micro-organisms or their metabolites is a promising environmentally friendly alternative to common fungicide-based technologies. Penicillium fungi which synthesize various biologically active compounds with a wide range of antimicrobial activity are of special interest as potential producers of antifungal biopreparations. The purpose of this study was the evaluation of the antifungal activity of a dry biomass of the Penicillium chrysogenum VKPM F-4876D strain (DMP), both individually and combined with commercial azoxystrobin-, fludioxonil-, difenoconazole-, and tebuconazole-based fungicides commonly used to control early blight, towards Alternaria solani, an infectious agent of this potato disease. The study was performed under in vitro (cultivation on solid and liquid media) and in vivo (detached potato leaves) conditions. The cultivation of A. solani on agarized medium supplemented with 5 g/L of DMP caused significant morphological changes in pathogen colonies, whereas 7.5 g/L of DMP resulted in complete suppression of pathogen development. DMP addition to the liquid culture of A. solani significantly increased electrolyte release, i.e., impaired the cell membrane integrity in the pathogen. Combining DMP (1–2 g/L) with fungicides at a dose range of 0.01–10 mg/L resulted in significant in vitro growth inhibition of A. solani. The best result was obtained for the combination of DMP (1 g/L) with fludioxonil (1–5 mg/L) or tebuconazole (10 mg/L): a significant and prolonged antifungal effect (96–97% growth inhibition) was observed during the whole 14-day period of observation. The treatment of detached potato leaves with 1 g/L of DMP prior to artificial infection with A. solani resulted in a four-fold increase in the number of uninfected leaves and a two-fold reduction in the number of severely infected leaves compared to the control. These results demonstrate the possibility to develop an efficient environmentally friendly approach to manage potato early blight and provide prerequisites for the reduction in pesticide load on agrobiocoenoses, thus contributing to the restoration of ecological balance and the prevention of the emergence and spread of resistant pathogen strains.