Combining hydrogeochemical characterization and a hyperspectral reflectance measurement can provide knowledge for groundwater security under different conditions. In this study, comprehensive examinations of 173 groundwater samples were carried out in Makkah Al-Mukarramah Province, Saudi Arabia. Physicochemical parameters, water quality indices (WQIs), and spectral reflectance indices (SRIs) were combined to investigate water quality and controlling factors using multivariate modeling techniques, such as partial least-square regression (PLSR) and principal component regression (PCR). To measure water quality status, the drinking water quality index (DWQI), total dissolved solids (TDS), heavy metal index (HPI), contamination degree (Cd
), and pollution index (PI) were calculated. Standard analytical methods were used to assess nineteen physicochemical parameters. The typical values of ions and metals were as follows: Na2+
; and Cu > Fe > Al > Zn > Mn > Ni, respectively. The hydrogeochemical characteristics of the examined groundwater samples revealed that Ca-HCO3
, Na-Cl, mixed Ca-Mg-Cl-SO4
, and Na-Ca-HCO3
were the main mechanisms governing groundwater chemistry and quality under the load of seawater intrusion, weathering, and water-rock interaction. According to the WQIs results, the DWQI values revealed that 2.5% of groundwater samples were categorized as excellent, 18.0% as good, 28.0% as poor, 21.5% as extremely poor, and 30.0% as unfit for drinking. The HPI and Cd
values revealed that all groundwater samples had a low degree of contamination and better quality. Furthermore, the PI values showed that the groundwater resources were not affected by metals but were slightly affected by Mn in Wadi Fatimah due to rock–water interaction. Linear regression models demonstrated the significant relationships for the majority of SRIs paired with DWQI (R varied from −0.40 to 0. 75), and with TDS (R varied from 0.46 to 0.74) for the studied wadies. In general, the PLSR and PCR models provide better estimations for DWQI and TDS than the individual SRI. In conclusion, the grouping of WQIs, SRIs, PLSR, PCR, and GIS tools provides a clear image of groundwater suitability for drinking and its controlling elements.