To explore the role of quantitative Intravoxel incoherent motion (IVIM) parameters and their histogram analysis in characterizing changes in Osteosarcoma receiving neoadjuvant chemotherapy (NACT) and evaluating therapeutic response.Forty patients (N = 40; Male:Female = 30:10; Age = 17.7 ± 5.9years; Metastatic:localized = 17:23) with histologically confirmed Osteosarcoma treated with 3-cycles of NACT were analyzed prospectively. All patients underwent Diffusion weighted imaging (DWI) with 11 b-values (0-800 s/mm) using 1.5 T MRI scanner at pre-treatment (t0), after 1-cycle (t1) and after 3-cycles (t2) of NACT. Non-invasive response evaluation of NACT was performed using RECIST1.1 criteria. Apparent-diffusion-coefficient (ADC) and IVIM parameters - Diffusion-coefficient (D), Perfusion-coefficient (D*) & Perfusion-fraction (f) and their relative percentage changes from time-point t0-t1 (Δ2) and t0-t2 (Δ2) were evaluated and histogram analysis was performed at three time-points and compared with respect to RECIST1.1 scores.Using RECIST1.1 criteria, 11 (27.5%), 21 (52.5%) and 8 (20%) patients were in Partial-responder (PR), Stable-disease (SD) and Progressive-disease (PD) groups respectively. Pre-NACT (t0), average ADC, D,D*&f in tumor volume were 1.36 ± 0.33 × 10 mm/s, 1.3 ± 0.3 × 10 mm/s, 28.44 ± 10.34 × 10 mm/s & 13.95 ± 2.83% respectively. Using ANOVA test, during NACT (t1, t2), D*-variance (p = 0.038, 0.003) and f-skewness (p = 0.03, 0.03) and at t2, D*-entropy (p = 0.001) and f-entropy (p = 0.002) and their Δ2 changes (p = 0.001, 0.003) were statistically significant among response groups. At t1, D*-variance and f-skewness jointly showed AUC = 0.77 & 0.74 in classifying PR (Sensitivity = 73%; Specificity = 70%) and SD (Sensitivity = 74; Specificity = 75%) groups respectively in patient cohort. Δ1 & Δ2 changes of D*-mean, D*-variance, D*-entropy and f-entropy correlated well (0.5-0.6) with tumor-diameter and tumor-volume changes.Quantitative IVIM parameters, especially D* &f and their histogram analysis were informative and can be used as noninvasive surrogate markers for early response assessment during the course of NACT in Osteosarcoma.