Abstract Objectives Almond consumption can improve cardiometabolic health. However, the mechanisms underlying those physiological changes are not well characterized. This study explored the effects of consuming a snack of almonds for 8 weeks on changes in omics profiles in young adults. Methods Newly enrolled, college students (n = 73, age: 18–19 years, BMI: 18–41 kg/m2) were randomly assigned to consume a morning snack, i.e., either almonds (2 oz./d, n = 38) or an isocaloric control snack of graham crackers (325 kcal/d, n = 35) daily for 8 weeks (Clinical trials: NCT03084003). Blood samples were collected every 4 weeks over the 8 week intervention. Metabolite abundances in the serum were quantified by hydrophilic Interaction chromatography (HILIC) quadrupole (Q) time-of-flight (TOF) mass spectrometry (MS/MS), gas chromatography time-of-flight (GCTOF) MS, and CSH-ESI (electrospray) QTOF MS/MS. Data were reported as quantitative ion peak heights and were normalized by systematic error removal using random forest (SERRF) normalization. The baseline-adjusted means of the almond and cracker groups at week 8 were analyzed using ChemRICH which is a chemical similarity enrichment analysis software for metabolomics datasets that uses medical subject headings and Tanimoto substructure chemical similarity coefficients to cluster metabolites into non-overlapping chemical groups. Statistically significant p-values for clusters were obtained by self-contained Kolmogorov–Smirnov tests. Results Out of the 5716 features detected, 857 were identified as known compounds. ChemRICH mapped 660 of the identified metabolites to 63 nonoverlapping chemical classes, of which 2 were found to be significantly different between the almond and cracker groups (false discovery rate adjusted P value (FDR) < 0.05). Almond snacking for 8 weeks was associated with altered unsaturated lipid metabolism represented by significantly increased levels of unsaturated triglycerides and unsaturated lysophosphatidylcholines compared with cracker snacking (cluster FDR < 0.05). Conclusions These findings indicate that almond and cracker snacking for 8 weeks differentially altered lipid metabolism. Funding Sources Research supported by Almond Board of California and NIH-NIMHD.