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Simple Summary: Renal cell carcinoma (RCC) is one of the most common cancer types. However, the lack of clinical symptoms and validated biomarkers for early stage RCC prevent timely disease diagnosis. The study was focused on revealing potential low molecular biomarkers for early-stage RCC. The untargeted direct injection mass spectrometry-based metabolite profiling of blood plasma samples from non-cancer volunteers (control) and RCC patients (early stages of clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chrRCC), and advanced stages of ccRCC) was performed. A set of metabolites with diagnostic power for the early stages of ccRCC was detected. Early diagnostics significantly improves the survival of patients with renal cell carcinoma (RCC), which is the prevailing type of adult kidney cancer. However, the absence of clinically obvious symptoms and effective screening strategies at the early stages result to disease progression and survival rate reducing. The study was focused on revealing of potential low molecular biomarkers for early-stage RCC. The untargeted direct injection mass spectrometry-based metabolite profiling of blood plasma samples from 51 non-cancer volunteers (control) and 78 patients with different RCC subtypes and stages (early stages of clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chrRCC) and advanced stages of ccRCC) was performed. Comparative analysis of the blood plasma metabolites between the control and cancer groups provided the detection of metabolites associated with different tumor stages. The designed model based on the revealed metabolites demonstrated high diagnostic power and accuracy. Overall, using the metabolomics approach the study revealed the metabolites demonstrating a high value for design of plasma-based test to improve early ccRCC diagnosis. [ABSTRACT FROM AUTHOR]