Whether BMI and the competing waist circumference (WC)-based anthropometric indices are associated with obesity-related single-nucleotide polymorphisms (SNPs) is as yet unknown. The current study aimed to evaluate the anthropometric indices (fat mass index, body shape index, visceral adiposity index, relative fat mass, body roundness index, and conicity index) during a weight loss intervention in 36 obese individuals. Blood biochemical parameters (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides) and three SNPs (FTO rs9939609, TFAP2B rs987237, and PLIN1 rs894160) were assessed in 22 women and 14 men (35.58 ± 9.85 years, BMI 35.04 ± 3.80 kg/m2) who completed a 12-month balanced energy-restricted diet weight loss program. Body composition was assessed via bioelectrical impedance (SECA mBCA515). At the end of the weight loss intervention, all anthropometric indices were significantly reduced (p < 0.05). For the SNP FTO rs9939609, the higher risk allele (A) was characteristic of 88.9% of the study group, in which 10 participants (27.8%) were homozygous. We found a similar distribution of alleles in TFAP2B and PLIN1. Heterozygous genotypes in FTO rs9939609 and TFAP2B rs987237 were predisposed to significant reductions in WC-based novel anthropometric indices during weight loss. The influence of PLIN1 rs894160 polymorphisms on the changes in the analyzed indices during weight loss has not been documented in the present study.