Geochemical exploration for rare metals, specifically lithium, is essential on a regional scale based on their demand and consumption in recent years. The main objective of this study was to delineate lithium anomalies in regional exploration utilizing the geochemical mapping prospectivity index (GMPI), staged factor analysis (SFA), and a concentration-number (C-N) fractal model based on stream sediments. The case study area is 26000 km2 and is located in the Khorasan Razavi province (NE Iran). In addition, rock samples were used to validate the Li anomalies identified. Results derived via the SFA show that Li was located on a factor denoted as F1-3 with Be, Cs, F, Nb, Sn, Th, U and W, which was used for calculation of the GMPI values. The GMPI data were classified by the C-N fractal method for determination of the Li anomalies. The main anomalies with GMPI ≥ 0.7 and Li ≥ 48 ppm were situated in the SE, SW, north and south parts of the study region. Li grades of rock samples were categorized by the C-N fractal technique for validation of F2-2 anomalies using a log-ratio matrix. The main anomalies were correlated with related lithological units of Li mineralization types. This correlation indicates that the main GMPI–Li anomalies are associated with granitic–pegmatitic units in the central and SE parts, and overlap with clay minerals in the northern and southern sectors of this region. There is good potential for Li mineralization as demonstrated by this hybrid method.