Abstract Background Previous anatomic studies have provided valuable information on the 2-dimensional course of the angular segment of the facial artery in the midface and its arterial connections. The third dimension (ie, the depth of the artery) is less well characterized. Objectives The objective of the present study was to describe the 3-dimensional pathway of the angular segment of the facial artery and its relationship to the muscles of facial expression. Methods The bilateral location and the depth of the midfacial segment of the facial artery was measured utilizing multi-planar computed tomographic image analyses obtained from contrast agent-enhanced cranial computed tomographic scans of 156 Caucasians aged a of 45.19 ± 18.7 years and with a mean body mass index of 25.05 ± 4.9 kg/m2. Results At the nasal ala, the mean depth of the main arterial trunk was 13.7 ± 3.7 mm (range, 2.7-25.0 mm), whereas at the medial canthus it was 1.02 ± 0.62 mm (range, 1.0-3.0 mm). This was reflected by the arteries’ relationship to the midfacial muscles: at the nasal ala superficial to levator anguli oris in 62.0% but deep to the levator labii superioris alaeque nasi in 53.6%; at the medial canthus superficial to the levator labii superioris alaeque nasi in 83.1% and superficial to the orbicularis oculi in 82.7%. Conclusions The results presented herein confirm the high variability in the course of the angular segment of the facial artery. Various arterial pathways have been identified providing evidence that, in the midface, there is no guaranteed safe location for minimally invasive procedures.