Porphyrin-lipid nanoparticles (Por-NPs) have unrealized potential for atherosclerosis. Por-NPs incorporate porphyrin-lipid which permits fluorescence imaging and chelates Copper-64 (⁶⁴Cu) for positron emission tomography (PET) imaging. Their outer shell contains a short peptide 'R4F' that enables macrophage targeting and therapeutic effects. Accordingly, this study investigates the simultaneous diagnostic and therapeutic properties of Por-NPs in atherosclerosis. <i>In vitro</i>, Por-NPs were found to be internalized by immortalised bone marrow-derived macrophages (iBMDMs), visualized via fluorescence microscopy and flow cytometry. Por-NPs also increased cholesterol efflux from [³H]-cholesterol-loaded iBMDMs, (49 %, <i>P</i> < 0.05). Incubation of iBMDMs with Por-NPs reduced mRNA levels of inflammatory mediators <i>Il1b</i> (88 %), <i>Il18</i> (54 %) <i>Ccl5</i> (75 %) and <i>Ccl17</i> (92 %), and protein secretion of IL-1β (69 %), CCL5 (82 %) and CCL17 (94 %), <i>P</i> < 0.05. Por-NPs suppressed inflammasome components <i>Nlrp3</i> (69 %) and <i>Asc</i> (36 %), <i>P</i> < 0.05. Studies using siRNA deletion of SR-B1 and methyl-β-cyclodextrin, revealed the anti-inflammatory properties of Por-NPs were independent of SR-B1 and cholesterol efflux. However, Por-NPs suppressed activation of inflammatory transcription factor NF-κB (53 %, <i>P</i> < 0.05). <i>In vivo</i>, in <i>Apoe</i> ^-/- mice, serial non-invasive PET imaging showed ⁶⁴Cu-labelled Por-NPs localised in hearts and detected increases in plaque size longitudinally with high-cholesterol diet. Por-NP fluorescence was visualized in aortic sinus plaques, co-localised with CD68⁺ macrophages, and by fluorescence IVIS imaging in aortic arch plaque. In two murine models, Por-NP-treated mice had smaller early-stage (22 %) and unstable plaques (52 %). Por-NP-treated mice had fewer circulating (32 %) and aortic (81 %) monocytes, and lower mRNA levels of aortic arch <i>Rela</i> (26 %) and <i>Nfkb1</i> (27 %), <i>P</i> < 0.05. Por-NPs detect plaques using multiple imaging modalities and exhibit atheroprotective effects, presenting as novel nanoscale theranostics for atherosclerosis.