Diatoms in general, and Thalassiosira weissflogii (T. weissflogii) in particular, are among the most ubiquitous phytoplanktonic species, while phosphorus (P) is an essential nutrient that limits productivity in many oceanic regimes. To investigate how T. weissflogii cultures grown under different P regimes are chemically altered before and during their prokaryotic degradation, T. weissflogii cells were cultivated under two contrasting P conditions; “P-stress” and “P-replete”. Biodegradation experiments were conducted in natural seawater comprising a natural prokaryotic community. The particulate fraction was monitored for 3 weeks for organic carbon (POC), nitrogen (PON), biogenic silica (bSiO2), total carbohydrates (PCHO) and individual monosaccharides, including prokaryotic counting. Results indicated that P-stress induced changes in the chemical composition of the T. weissflogii cells, causing a decrease in the Si/N (1.1–0.46) and Si/C (0.17–0.08) ratios. The “P-stress T. weissflogii” cells were characterized by high amounts of galactose (23% of PCHO), xylose (21%) and glucose (19%), compared to the “P-replete T. weissflogii” cells. The latter were dominated by ribose (20% of PCHO), further indicating the exhaustion of ribose-rich molecules (e.g., ATP) in T. weissflogii under “P-stress” conditions. The degradation experiments showed that bSiO2 produced under “P-stress” conditions dissolved more rapidly than bSiO2 formed under “P-replete” conditions, whereas POC and PON exhibited higher degradation rate constants in the “P-replete T. weissflogii” than in the “P-stress T. weissflogii” experiment. Overall, these observations show that submission of T. weissflogii to P-limitation results in changes in its initial biochemical composition, increased frustule dissolution rates, and decreases the degradation of T. weissflogii-organic matter by marine prokaryotes.