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Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms in the uridine diphosphate glucuronyl transferase (<i>UGT2B7</i>) gene on the pharmacokinetics and pharmacodynamics behavior of indapamide 1.5 mg sustained release. Forty-nine healthy volunteers aged 18–55 years were randomized into two groups; 25 volunteers were administered indapamide under fasting conditions and 24 under fed conditions. Genotyping of the <i>UGT2B7 rs7438135</i> and <i>rs11740316</i> was done before commencing the study using predesigned TaqMan assays. Results showed that food independently decreased the value of indapamide’ T_max by 5.5 h and increased the value of C_max by 8.7 ng/mL. On the other hand, all genetic variants of both <i>UGT2B7</i> SNPs had no significant impact on the values of T_max, C_max, and AUC_0–t; however, it was found that rs11740316 variant <i>AG</i> was correlated with a 2.8 h lower MRT_inf. Finally, BMI positively correlated with longer MRT_inf. It was concluded that none of <i>rs7438135</i>, <i>rs11740316</i>, or food had a significant impact on the pharmacodynamic properties. Food had a modest impact on indapamide C_max and T_max values, while there were unremarkable differences in safety and efficacy.